CLEANING HOLD TIME STUDIES
APIC Cleaning Validation guideline states, “For both dedicated and multi-product
facilities, the frequency with which the cleaning procedure should be performed
should be validated to assess the risks related to potential degradation and
microbiological contamination’’.
Eudralex Annex 15 states, “The influence of the
storage time before cleaning and the time between cleaning and use taken into
account to define (dirty and clean) hold times should be assessed during
cleaning validation.
The World Health Organization (WHO) states,
“The period and conditions for storage of unclean equipment
before cleaning, and the time between cleaning and equipment reuse, should form
part of the validation of cleaning procedures”.
Health Canada states, “Time-frames
for the storage of unclean equipment, prior to commencement of cleaning, as
well as time frames and conditions for the storage of cleaned equipment should
be established”
PICS
states, “The
period and when appropriate, conditions of storage of equipment before cleaning
and the time between cleaning and equipment reuse, should form” part of the validation of cleaning procedures.
This is to provide confidence that routine cleaning and storage of equipment
does not allow microbial proliferation”.
The US FDA
Guide to Inspections Validation of Cleaning Process states, “Always check for the
presence of an often critical element in the documentation of the cleaning
processes; identifying and controlling the length of time between the end of
processing and each cleaning step. This is especially important for topicals,
suspensions, and bulk drug operations. In such operations, the drying of
residues will directly affect the efficiency of a cleaning process”.
Dirty Equipment Hold Time (DEHT):
DEHT is
defined as the time between end of use of the equipment and the start of
equipment cleaning.
The
purpose of validating the dirty equipment hold time is to provide
evidence that the length of time equipment may sit idle prior to cleaning and
the condition under which this storage occurs will not challenge the ability of
the cleaning process to remove process or microbial residues.
Keeping residues on equipment surfaces prolonged time may make them harder to remove and
thus challenge the ability of the cleaning process to clean the residuals. Also,
permitting process residues, media, or solutions to settle in equipment or open to environment may allow to occur microbial
proliferation that challenges the capability of the cleaning
cycle to successfully remove microbial contamination.
Methodology
for Validation:
Held
dirty equipment after processing for an extended period of time (for example 24
hrs.) before cleaning and monitor chemical & microbial contaminants at
specified periods (for example 0 hrs., 8 hrs., 12 hrs., 16 hrs., and 24 hrs.)
- It would be ideal to discuss with manufacturing team to identify longest time interval that equipment would be uncleaned after usage.
- It would be ideal to use worst case approach to select equipment / equipment train for the study.
- Rinse & swab sampling techniques to be used for monitoring of both active and cleaning agent contents along with total microbial count from swab samples.
Clean Equipment Hold Time (DEHT):
CEHT is
defined as the time between completion of the cleaning of the equipment and the
equipment re-use.
The
purpose of validating the clean equipment hold time is that nothing
stays clean forever. There are possibilities for re-contamination of cleaned
equipment through endogenous sources (growth of microorganism already present
in equipment) as well as exogenous sources (such as entry of external
contamination in to equipment)
If
equipment is stored wet for a sufficient time, there is a reasonable
probability microbes will readily grow to an unacceptable level and that make
equipment unsuitable for manufacturing usage.
Methodology
for Validation:
Held
Clean equipment for an extended period of time (for example 7 days) before re-use
and monitor chemical & microbial contaminants at specified periods (for
example 1st day, 2nd day, 3rd day, 4th
day, 5th day, 6th day and 7th day.)
- It would be ideal to discuss with manufacturing team to identify longest time interval that equipment would be unused after cleaning.
- It
would be ideal to use worst case approach to select equipment / equipment train
for the study.
- Rinse
& swab sampling techniques to be used for monitoring of both active and
cleaning agent contents along with total microbial count from swab samples.
Refer below for other details.
THE STORY OF NITROSAMINE IMPURITIES & VALSARTAN RECALLS
The word Nitrosamine impurities are blasted in the pharmaceutical industry from July 2018 after identifying the traces of the toxic nitrosamine genotoxic impurities like N-nitrosodimethylamine (NDMA) & nitrosodiethylamine (NDEA) in the APIs made by china manufacturer Zhejiang Huahai, Zhejiang Tianyu, and Indian manufacturer Hetero lab manufactures generic sartans, the angiotensin inhibitor blockers (ARBs), a generic valsartan distributed by Torrent Pharmaceuticals prescribed to some patients to treat high blood pressure.
During investigation also noticed that
- Nitroso amine impurities are likely to be present in the batches since 2012 when a change of process was made.
- NDMA was unexpected therefore not controlled
- Significant levels found.
- NDMA is a possible carcinogen for Humans.
Even though initially NDMA identified, number of following Nitroso impurities identified as part of further investigation.
NDMA- Nitrosodimethylamine
NDEA- Nitrosodiethylamine
NDBA- Nitrosodibutylamine
NMBA- Nitrosobutyl amino butyric acid
NDIPA- Nitrosodiisopropylamine
NIPEA- Nitrosoisopropyl ethylamine
Origin of NDMA/NDEA:
Regulatory firms identified that Indian Hyderabad based solvent recovery firm Lantech Pharmaceutical processing methods are left open the chances of cross-contamination of solvents that contained the impurities known as NDMA & NDEA and there is a potential to contain nitrosamine impurities through mix-up & cross-contamination for all products manufactured in their facility.
The chemical structure of Angiotensin II receptor blockers (ARBs) contains a tetrazole group. It is apparent that tetrazole ring formations, coupled with certain manufacturing conditions in presence of DMF, produce these types of impurities in drug substance intermediates used in sartans. Other tetrazole ring formations produce APIs like Olmesartan, candesartan, irbesartan, and losartan. The impurity may also roll over to other compounds normally known as “zoles,” such as omeprazole, etc.
Impacted Products:
Valsartan, Losartan, Irbesartan, almost all sartans expect Telmisaratn and ranitidine …etc
Currently identified all root causes for the presence of Nitrosamines:
Currently identified sources of nitrosamine impurities are listed below:
- Use of nitrosating agents like sodium nitrite (NaNO2) in the presence of secondary (2°), tertiary (3°) amines, or quaternary (4°) ammonium salts within the same or different process steps (if carryover can occur).
- Use of nitrosating agents like sodium nitrite (NaNO2), along with catalysts, solvents, and reagents, that are likely to degradation to secondary (2°) or tertiary (3°) amines, within the same or different process steps (if carryover can occur).
- Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents, and catalysts).
- Use of recovered materials (e.g. solvents, reagents, and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and routine recovery processes carried out in non-dedicated equipment.
- Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials that may allow nitrosamine formation.
- Cross-contamination due to different processes run on the same line and due to operator-related errors such as inadequate phase separations.
- Degradation of starting materials, intermediates, and drug substances, including those induced by inborn reactivity in combination with carry-over of nitrosating agents like NaNo2 could potentially occur also during finished product formulation or storage.
- MAH observed the use of certain packaging materials (containing nitrocellulose printing primer) with lidding foil that may react with amines present in printing ink to produce nitrosamines which would then transfer to the product under certain packaging process conditions. (e.g. during vaporization & condensation of heat-sealing blistering processes may produce nitrosamines then transfer onto the drug product) .
How to perform risk evaluation for Nitrosamine Impurities:
- MAHs along with API and finished product manufacturers are required to perform risk assessment using ICH Q9 & ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing processes for active (API) substances should be applied.
- Nitrosamine impurity formation risk should be assessed from the development phase of the API/ Finished product manufacturing process.
- The risk of nitrosamine formation should be assessed w.r.t API process, reagents, solvents, catalysts, starting materials, intermediates, impurities, and degradants.
- The potential risk of nitrosamine contamination (e.g. from recovered materials such as catalysts, reagents, solvents, equipment, degradation, starting materials, or intermediates) should be assessed.
- Is there any potential of nitrosamine formation during the manufacture of the finished product and/or during storage throughout its shelf life should be assessed.
- A representative number of samples of the relevant starting material, intermediate, API, or finished product should be tested with an appropriately validated analytical method for the evaluation of nitrosamine impurities. The number of batches/samples tested should be scientifically justified.
Limits for nitrosamine Impurities:
For reference, consuming up to 0.096 micrograms or 0.32 parts per million (ppm) of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure. (which means, if a person consumes 0.32ppm / 0.096mg of NDMA for the entire life of 70 years)
The regulatory requirement from the industry:
- All authorized human medicinal products containing chemically synthesized APIs are to be studied, including over-the-counter (OTC) and generics products. However, in view of a large number of authorized products, MAHs should use a risk-based approach and prioritize their evaluations and confirmatory testing.
- MAHs should prioritize products in order to establish the sequence in which their products are to be evaluated. For the purposes, MAHs may consider factors such as the maximum daily dose is taken, duration of treatment, therapeutic indication, and the number of patients treated. For example, medicinal products with a higher daily dose, and those for chronic use may take priority.
- In order to undertake the analysis of the identified medicinal products at risk, MAHs can also use tools such as Failure Mode Effects Analysis (FMEA) and Failure Mode, Effects, and Criticality Analysis (FMECA) as stated in the ICH Q9 quality guideline on quality risk management.
- If MAHs identify that changes are necessary in their production process and/or product formulation, they should communicate with competent authorities in order to assess the type of variation required and to submit one as needed in a timely manner.
- This risk evaluation must be concluded within six months after the regulatory statement was published.
- The risk evaluation’s documentation must not be submitted, though it is to be made available upon request.
- If a risk of potential contamination has been detected, the marketing authorization holder should go for conformity testing via validated and appropriately sensitive analytical methods.
- If nitrosamine is found, the competent authorities are to be informed immediately, irrespective of the amount detected.
ANALYTICAL METHOD AND ITS SUITABILITY
Analytical method or procedure:
The analytical procedure refers to the procedure or steps necessary to perform each analytical test.This may include but is not limited to: the method & instrument parameters, the sample/ reference standard & the reagents preparations, use of the apparatus, dilutions required, generation of the calibration curve, use of the formulae for the calculation, etc.
In-house developed Analytical Method:
The analytical method that was not listed in any of the pharmacopeias like USP, EP, IP, and JP and developed as per the internal requirements.
All the in-house developed analytical methods should be validated and transferred to the laboratories where commercial batch analysis shall be performed.
Compendial or Pharmacopoeial Analytical Method:
The analytical method that was listed in any of the pharmacopeias like USP, EP, IP, and JP…etc.
All the compendial or pharmacopoeial methods considered to be validated and only verification to be performed to demonstrate that the procedure is suitable for the intended purpose.
If a method is listed in pharmacopeias like USP, EP, IP, and JP…etc, but you want to use the same method with modification or completely different methods then you should show method equivalency between your method & the method listed in monographs.
Analytical method Validation:
Analytical method validation is the process of demonstrating that the analytical procedure is suitable for its intended purpose.
The following characteristics shall be considered for the demonstration of method suitability for its intended purpose.
Method
Validation Parameter
|
Purpose
|
Procedure
|
|
Specificity |
Interference Study. To verify whether the interested peak is spectrally pure or not?i.e. peak response is due to a single component only and no co-elutions exist. |
Specificity of the method shall be demonstrated by analyzing the sample spiked with all known impurities at specification level and showing that no interference of impurities at the retention time of main peaks. |
|
Precision |
To verify the degree of repeatability of the analytical method under normal conditions. Usually expressed as a standard deviation. Minimum of six determinations at 100% of the test or target concentration |
Repeatability |
Repeatability is the results of the method operating over a short time interval under the same conditions |
Reproducibility |
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology). |
||
Intermediate Precision |
Intermediate precision is the result from within lab variations due to random events such as different days, analysts, equipment, etc. If reproducibility is performed then intermediate precision not required. |
||
Accuracy |
To verify the exactness of the analytical method or closeness of the accepted reference value and actual value found from the experiment. |
Collecting
data from a minimum of nine determinations over a minimum of three
concentration levels covering the specified range (for example, three
concentrations, and three replicates each).
|
|
Limit of Detection |
The lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. |
S/N ratio is determined by comparing signals from the analyte of known low concentrations samples with blank samples and determining the minimum concentration at which the analyte can be consistently detected.
S/N ratio between 3:1 or 2:1 is considered as acceptable for estimating the detection limit.
|
|
Limit of Quantitation |
The lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. And is used particularly for the determination of impurities and/or degradation products |
Determination of the S/N ratio is done by comparing measured signals from known low concentrations samples of an analyte with those of blank samples and by establishing the minimum concentration at which the analyte can be consistently quantified.
A typical S/N ratio is 10:1
|
|
Linearity |
Ability to get test results within the given range that are proportional to the concentration (amount) of the analyte in the sample |
Guidelines specify a minimum of five concentration levels, along with certain minimum specified ranges.For the assay, the minimum specified range is from 80-120% of the target concentration.
For an impurity test, the minimum range is from the
reporting level of each impurity, to 120% of the specification. (For toxic or
more potent impurities, the range should be commensurate with the controlled
level.)
|
|
Range |
lower and upper concentration (amounts) interval of analyte in the sample (including lower & upper concentrations) for which it has been proven that the analytical the procedure has a suitable level of precision, accuracy, and linearity. |
||
Robustness |
The measure of analytical method capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage. |
The robustness of an analytical method is assessed by deliberately varying method parameters such as temperature, ionic strength, pH & % organic etc., and evaluating the effect (if any) on the results of the analytical method. |
|
Ruggedness |
The degree of reproducibility of the results obtained under a variety of conditions, expressed as %RSD. |
These conditions include different laboratories, analysts,
instruments, reagents, days, etc.
|
|
Solution Stability |
To establish the stability of the sample and standard solutions |
Sample & Standard solutions to be analyzed at periodic times. |
|
System Suitability |
To verify the system suitability parameters |
All system suitability parameter to be verified as per respective testing procedure. |
|
Analytical method Transfer:
Analytical method transfer is a documented process that qualifies a laboratory to use an analytical test procedure that originated in another laboratory thus ensuring that the laboratory has the procedural knowledge and ability to perform the test.
If the receiving laboratory participated in the collaborative study (Reproducibility as part of the precision study) during the validation of the analytical method, then the same shall be reported as Co-Validation and the laboratory can be considered as qualified for use of analytical test method.
If the receiving laboratory has not participated in the Validation study then method transfer activity shall be performed as follows to qualify a lab to use the test method.
In-direct method Transfer (Inter Lab):
Analysis of the same samples (Single batch), six times at both the transferring unit & receiving unit by using the same analytical method. However, the transferring unit can consider data from the method validation study.
Direct method Transfer (Inter Lab):
Analysis of the same samples (Single batch), six times by both the analyst of the transferring unit & receiving unit by using the same analytical method at the receiving laboratory.
Analytical method Verification:
Users should have the appropriate experience, knowledge, and training to understand and be able to perform the compendial procedures as written.
Verification should be conducted for all compendial procedures in a way such that the verification results will provide assurance that the procedure will perform consistently as intended.
Verification requirements should be based on an assessment of the complexity of both the procedure and the material to which the procedure is applied.
Although complete revalidation of a compendial method is not required to verify the suitability of the method under actual conditions of use, some of the analytical performance characteristics listed at the analytical method validation section may be used for the verification process.
Only those characteristics that are considered to be appropriate for the verification of the particular method need to be evaluated. The degree and extent of the verification process may depend on the level of training and experience of the user, on the type of procedure and its associated equipment or instrumentation, on the specific procedural steps, and on which article(s) are being tested.
Routinely performed basic compendial test procedures do not require verification unless there is an indication that the procedure is not appropriate for the article under test. Examples include, but are not limited to, residue on ignition, loss on drying, several wet analysis procedures such as simple instrumental methods such as pH measurements & acid value. However, for the application of already established routine procedures to compendial articles tested for the first time, it is recommended that consideration be given to any new or different sample handling or solution preparation requirements.
Analytical method Equivalency:
Equivalency demonstrates the sameness of two analytical methods.
Method equivalency comes in to picture whenever you want to use different methods against to monograph method and/or already filed methods during product registrations.
The goal of method equivalency is to demonstrate acceptable method performance by comparison of a specific set of results (e.g., an assay). I.e. the method proposed is equally capable as a monograph / already filed method to analyze the interesting samples.
PROCESS VALIDATION
Validation:
Validation is the action of proving or declaring something (Procedure, process & equipment etc) that actually capable to deliver expected results and is officially valid.
Process Validation:
Process validation is the action of proving or declaring that the established process is capable to deliver expected results and is officially valid.
Objective of process Validation
To generate a documented evidence, from the evaluation of data from process design stage through commercial production, that provides a high degree of assurance that a specific process will consistently results in a product that meets predetermined specification and quality characteristics.
Process validation should not be viewed as a one-off event. Process validation incorporates a life cycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.
The objective of process validation consists of following major steps.
- The process design is evaluated to show that it is reproducible,
- The commercial manufacturing process is defined and controlled,
- Ongoing assurance is gained to show that the process remains in a state of control.
Types of Process Validation:
Process validation mainly divided in to following four types.
a) Prospective Validation (Premarket Validation)
b) Concurrent Validation
c) Retrospective Validation
d) Re-validation
A) Prospective Validation (Premarket Validation)
This approach to validation is normally undertaken during development stage by means of a risk analysis of the process, generally whenever the process for a new formula (or within a new facility) must be validated before routine pharmaceutical production commences.
In fact, validation of a process by this approach often leads to transfer of the manufacturing process from the development function to production.
Prospective validation should be completed before commercial distribution.
B) Concurrent Validation:
Concurrent validation is carried out during normal production.
This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process.
The first three production-scale batches must be monitored as comprehensively as possible. The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.
This validation generally used for batches produced infrequently and/or batches are produced by a validated process that has been modified.
Prior to the completion of concurrent validation, batches can be released.
C) Retrospective Validation: (Regulatory not considering this as on date)
Retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process.
Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company.
Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule.
Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
D) Re-Validation:
Re-validation means repeating the original validation effort or any part of it, and includes investigative review of existing performance data.
Re validation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.
Possible reasons for re-validation:
a) Periodic re-validation
b) Re-validation after change in the starting material
c) Re-validation after change in the packing material
d) Re-validation after change in the process
e) Re-validation after change in the equipment or measuring instrument
f) Re-validation after change in the production area or supporting system.
g) Re-validation after significant change in the batch size
Traditional Approach of Process Validation:
Traditionally process validation was focused on testing, instrument qualification, and process robustness and repeatability.
Traditional approach includes following four elements
Design Qualification (DQ)
Installation Qualification (IQ)
Operational Qualification (OQ)
Process Validation (PV)
In this approach the manufacturer performs a minimum of 3 commercial batches for validation and if successful, the validation effort is considered complete, and manufacturer could then routinely use the process to produce the product, without further process validation and there was no requirement to perform any further ongoing life cycle validation efforts.
Modern Approach of Process Validation (Life Cycle Approach):
Against to traditional approach, the current enhanced process validation approach consists three phase continuous process with ongoing effort for the entire life cycle of the product called as life cycle approach.
Phase I. Process design
Phase II. Qualification and process verification
Phase IIA. Qualification
Phase IIB. Continuous process performance verification
Phase III. Continued process verification
Phase I. Process design:
The goal of this stage is to design a process suitable for routine commercial manufacturing process that can consistently deliver a product that meets its quality attributes.
Process design should normally cover design of experiments, product & process development, and the manufacture of products for use in clinical trials, pilot-scale batches and technology transfer.
Process design should cover aspects for the selection of materials, expected production variation, selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in-process controls, tests, inspection and its suitability for the control strategy.
Product & Process development:
The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product.
It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design.
At the completion of this stage technology transfer package containing information sufficient to plan and manufacture scale up & exhibit batches shall be made available.
A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel, and formally accepted by manufacturing, engineering and quality personnel, should be prepared.
Such a document may include information, desired clinical performance, bills of materials, approved suppliers, finished product specifications and test methods, in-process testing specifications, equipment recommendations, master batch production records, master batch packaging records, stability reports, critical quality attributes, critical process parameters, batch comparisons, data on formulation batches, stability batches, clinical/ bio batches and scale-up batches. These documents should be readily available to the manufacturing site.
Scale up activities:
The aim of scale up activities is to assess the impact of scaling up of manufacturing process on the performance of manufacturing process and product quality.
At the completion of this stage, control strategy of for manufacturing process for validation batches should be made available.
A scale up report, formally reviewed and approved by research and development personnel, manufacturing and quality personnel, should be prepared.
Such a document may include information related to Product, Manufacturing process, process evaluation and recommended control strategy with conclusion as a minimum criteria.
— As part of the process validation life cycle some process validation studies may be conducted on pilot-scale batches (corresponding to at least 10% or 100 000 units, whichever is the greater) of the production scale. Where the batch size is smaller and/or where the process is tailored to the geometry and capacity of specific equipment, it may be necessary to provide production-scale validation data.
— The number of batches included in the process design stage of validation should be appropriate and sufficient to include (but not be limited to) the expected variations in starting materials, and confirm the suitability of the equipment and manufacturing technology
— Manufacturers should define the stage at which the product is considered to be validated and the basis on which that decision was made. It should include a justification for the number of batches used based on the complexity and expected variability of the process.
Phase II. Qualification and process verification:
This phase consist of following sub-phases.
Phase IIa: Qualification of personnel, premises, utilities, and equipment’s where commercial scale batches will be manufactured.
Phase IIb: Continuous process performance verification.
Phase IIa:
Personnel Premises, utilities, support systems and equipment should be appropriately qualified before process performance verification (as part of validation) is started.
In a traditional approach, stages of qualification may include design, installation, operational and performance qualification.
In some cases process validation may be conducted concurrently with performance qualification.
Phase IIb:
After completion of qualification, commercial batches should be subjected to continuous process performance verification as part of process validation. It should confirm that scale up in batch size do not adversely affect the characteristics of a product.
Demonstrates that a process that operates within the predefined specified parameters consistently produces a product which meets all its critical quality attributes (CQAs) and control strategy requirements
The process should be verified on commercial-scale batches prior to marketing of the product.
Extensive in-line or at-line controls should be used to monitor process performance and product quality in a timely manner. In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production.
Manufacturers should describe the appropriateness and feasibility of the CPV strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed.
It is expected that additional monitoring for the first commercial batches should be done where continuous process verification is implemented.
Phase III. Continued process verification:
Manufacturers should monitor product quality of commercial batches after completion of Phase I and Phase II of process validation. This will provide evidence that a state of control is maintained throughout the product life-cycle
Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement.
Process trends such as the quality of incoming materials or components, in-process and finished product results and non-conformances should be collected and assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy.
The extent and frequency of ongoing process validation should be reviewed periodically and modified if appropriate throughout the product life-cycle.
Traditionally process validation was focused on testing, instrument qualification, and process robustness and repeatability.
Traditional approach includes following four elements
Design Qualification (DQ)
Installation Qualification (IQ)
Operational Qualification (OQ)
Process Validation (PV)
In this approach the manufacturer performs a minimum of 3 commercial batches for validation and if successful, the validation effort is considered complete, and manufacturer could then routinely use the process to produce the product, without further process validation and there was no requirement to perform any further ongoing life cycle validation efforts.
Modern Approach of Process Validation (Life Cycle Approach):
Against to traditional approach, the current enhanced process validation approach consists three phase continuous process with ongoing effort for the entire life cycle of the product called as life cycle approach.
Phase I. Process design
Phase II. Qualification and process verification
Phase IIA. Qualification
Phase IIB. Continuous process performance verification
Phase III. Continued process verification
Phase I. Process design:
The goal of this stage is to design a process suitable for routine commercial manufacturing process that can consistently deliver a product that meets its quality attributes.
Process design should normally cover design of experiments, product & process development, and the manufacture of products for use in clinical trials, pilot-scale batches and technology transfer.
Process design should cover aspects for the selection of materials, expected production variation, selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in-process controls, tests, inspection and its suitability for the control strategy.
Product & Process development:
The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product.
It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design.
At the completion of this stage technology transfer package containing information sufficient to plan and manufacture scale up & exhibit batches shall be made available.
A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel, and formally accepted by manufacturing, engineering and quality personnel, should be prepared.
Such a document may include information, desired clinical performance, bills of materials, approved suppliers, finished product specifications and test methods, in-process testing specifications, equipment recommendations, master batch production records, master batch packaging records, stability reports, critical quality attributes, critical process parameters, batch comparisons, data on formulation batches, stability batches, clinical/ bio batches and scale-up batches. These documents should be readily available to the manufacturing site.
Scale up activities:
The aim of scale up activities is to assess the impact of scaling up of manufacturing process on the performance of manufacturing process and product quality.
At the completion of this stage, control strategy of for manufacturing process for validation batches should be made available.
A scale up report, formally reviewed and approved by research and development personnel, manufacturing and quality personnel, should be prepared.
Such a document may include information related to Product, Manufacturing process, process evaluation and recommended control strategy with conclusion as a minimum criteria.
— As part of the process validation life cycle some process validation studies may be conducted on pilot-scale batches (corresponding to at least 10% or 100 000 units, whichever is the greater) of the production scale. Where the batch size is smaller and/or where the process is tailored to the geometry and capacity of specific equipment, it may be necessary to provide production-scale validation data. — The number of batches included in the process design stage of validation should be appropriate and sufficient to include (but not be limited to) the expected variations in starting materials, and confirm the suitability of the equipment and manufacturing technology — Manufacturers should define the stage at which the product is considered to be validated and the basis on which that decision was made. It should include a justification for the number of batches used based on the complexity and expected variability of the process.
Phase II. Qualification and process verification:
This phase consist of following sub-phases.
Phase IIa: Qualification of personnel, premises, utilities, and equipment’s where commercial scale batches will be manufactured. Phase IIb: Continuous process performance verification.
Phase IIa:
Personnel Premises, utilities, support systems and equipment should be appropriately qualified before process performance verification (as part of validation) is started.
In a traditional approach, stages of qualification may include design, installation, operational and performance qualification.
In some cases process validation may be conducted concurrently with performance qualification.
Phase IIb:
After completion of qualification, commercial batches should be subjected to continuous process performance verification as part of process validation. It should confirm that scale up in batch size do not adversely affect the characteristics of a product.
Demonstrates that a process that operates within the predefined specified parameters consistently produces a product which meets all its critical quality attributes (CQAs) and control strategy requirements
The process should be verified on commercial-scale batches prior to marketing of the product.
Extensive in-line or at-line controls should be used to monitor process performance and product quality in a timely manner. In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production.
Manufacturers should describe the appropriateness and feasibility of the CPV strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed.
It is expected that additional monitoring for the first commercial batches should be done where continuous process verification is implemented.
Phase III. Continued process verification:
Manufacturers should monitor product quality of commercial batches after completion of Phase I and Phase II of process validation. This will provide evidence that a state of control is maintained throughout the product life-cycle
Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement.
Process trends such as the quality of incoming materials or components, in-process and finished product results and non-conformances should be collected and assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy.
The extent and frequency of ongoing process validation should be reviewed periodically and modified if appropriate throughout the product life-cycle.
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