Topic:– Process Validation

 

Definition:

“process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product .”

 

 

Guidelines – 1

–FDA/ICH, (CDER and CBER),

Q7-Good Manufacturing Practice for Active Pharmaceutical Ingredients, guidance for industry, August 2001.

–FDA/ICH, (CDER and CBER),

Q8(R2)-Pharmaceutical Development, guidance for industry, November 2009.

–FDA/ICH, (CDER and CBER),

Q9 -Quality Risk Management, guidance for industry, June 2006.

–FDA/ICH (CDER and CBER)

Q10- Pharmaceutical Quality System, guidance for industry, April 2009.

 

Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes process validation activities in three stages.

 

Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.

 

Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

  

Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

 

A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should:

–Understand the sources of variation.

–Detect the presence and degree of variation.

–Understand the impact of variation on the process and ultimately on product attributes.

–Control the variation in a manner commensurate with the risk it represents to the process and product.

 

FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211.

The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess…” (emphasis added). This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes.

 

Many products are single-source or involve complicated manufacturing processes. Homogeneity within a batch and consistency between batches are goals of process validation activities. Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health.

 

Stage 1 ― Process Design

Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.

Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. Process information available from product development activities can be leveraged in the process design stage. The functionality and limitations of commercial manufacturing equipment should be considered in the process design, as well as predicted contributions to variability posed by different component lots, production operators, environmental conditions, and measurement systems in the production setting. However, the full spectrum of input variability typical of commercial production is not generally known at this stage. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability.

Designing an efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained. Design of Experiment (DOE) studies can help develop process knowledge by revealing relationships, including multivariate interactions, between the variable inputs (e.g., component characteristics 13 or process parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments conducted while maximizing knowledge gained. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. FDA does not generally expect manufacturers to develop and test the process until it fails.

 

Stage 2 ― Process Qualification

During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ). During Stage 2, CGMP-compliant procedures must be followed. Successful completion of Stage 2 is necessary before commercial distribution.15 Products manufactured during this stage, if acceptable, can be released for distribution.

Qualification of utilities and equipment generally includes the following activities:

Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.

Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).

Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production.

The process performance qualification (PPQ) is the second element of Stage 2, process qualification. The PPQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. The approach to PPQ should be based on sound science and the manufacturer’s overall level of product and process understanding and demonstrable control. The cumulative data from all relevant studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should be used to establish the manufacturing conditions in the PPQ.

 

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. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch. The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process. Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to, volume of production, process complexity, level of process understanding, and experience with similar products and processes.

Stage 3 ― Continued Process Verification

The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control (§ 211.180(e)).

An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

Data gathered during this stage might suggest ways to improve and/or optimize the process by altering some aspect of the process or product, such as the operating conditions (ranges and set-points), process controls, component, or in-process material characteristics. A description of the planned change, a well- justified rationale for the change, an implementation plan, and quality unit approval before implementation must be documented (§ 211.100). Depending on how the proposed change might affect product quality, additional process design and process qualification activities could be warranted.

Maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a process remains in control. Once established, qualification status must be maintained through routine monitoring, maintenance, and calibration procedures and schedules (21 CFR part 211, subparts C and D).

The equipment and facility qualification data should be assessed periodically to determine whether re-qualification should be performed and the extent of that re-qualification. Maintenance and calibration frequency should be adjusted based on feedback from these activities.

 

 

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Disclaimer:-This presentation is solely prepared for training, sharing knowledge and information purpose only  collected from various guidelines and literature. The information presented here is only for reference purpose.

 

THANK YOU

Topic:–  Method Transfer

Definition:

The formal transfer of a test methodology is a required GMP process that qualifies a receiving laboratory to utilize a method that originated in a transferring laboratory.

This process is intended to ensure and document that the method performs as intended within the receiving laboratories environment.

Guidelines – 1

–USP <1224>TRANSFER OF ANALYTICAL PROCEDURES

–PDA TR57

–PDA TR65

–WHO guideline, No.961 Annex 7

–FDA Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics

 

The transfer of analytical procedures (TAP), also referred to as method transfer, is the documented process that qualifies a laboratory (the receiving unit) to use an analytical test procedure in another laboratory (the transferring unit), thus ensuring that the receiving unit has the procedural knowledge and ability to perform the transferred analytical procedure as intended.

 

 

In case of method transfer between two laboratories, different approaches may be taken to achieve the successful transfer of the procedure.

The approach is method transfer from the originating laboratory to the receiving laboratory.

The originating laboratory is defined as the laboratory that has developed and validated analytical method.

The receiving laboratory is defined as laboratory to which the analytical method to be transferred and that will participate in the method transfer studies.

In the method transfer, it is recommended that protocol be initiated with details of the experiments to be performed and acceptance criteria (in term of the difference between the means of the two laboratories) for passing the method transfer.

 

• Sending unit :- (SU)

Laboratory which the method originates from Development lab, routine QC lab, Originating lab, sending lab, transferring lab.

 

• Receiving unit:- (RU)

Laboratory which is being qualified on the validated method CRO, CMO, commercial unit, Receiving lab, transfer site.

 

Site Responsibilities :-
	Sending Unit (SU)	Receiving Unit (RU)
	Readiness assessment	Review transfer package
	Compile data/history	Evaluate internal gaps
	Organize training	Define training requirements
	Prepare transfer package	Provide resources
	Draft protocol/set acceptance criteria	Perform transfer and evaluate site results
	Provide samples	Provide data to SU
	Provide troubleshooting support	Approve transfer report
	Compare RU data against SU data
	Approve transfer report

 

Types of method transfer:-

Method transfer is defined as the process that qualifies a laboratory to use an analytical test procedure. The most common variations of method transfer are comparative testing, co-validation between two laboratories or sites, complete or partial method validation or revalidation, and the omission of formal transfer, sometimes termed the transfer waiver.

Comparative Testing:-

Comparative testing is the most common form of method transfer in the pharmaceutical industry.

It involves two or more laboratories or sites executing a preapproved protocol that details the criteria by which the receiving laboratory is deemed to be qualified to use the method(s) being transferred. The resulting data are compared with a set of predetermined acceptance criteria. Comparative testing also is used in other scenarios during development and Post approval, including other manufacturing sites and contract research organizations.

 

Co-validation:-

Between two laboratories, An alternative to comparative testing is to involve the receiving laboratory in the validation of the method to be transferred. By definition, a laboratory or site that performs validation experiments is qualified to run that method routinely. To perform such a transfer, one must identify which validation parameters are to be generated or challenged by the sending and receiving laboratories. A reasonable approach is to involve the receiving laboratory in the inter laboratory qualification, there by generating a matrix of data that summarizes the suitability of the testing site, analyst, date of analysis, and instrumentation for exercising the analytical test procedures. By fully describing the experimental design for the validation exercise and including the resulting data in the method validation report, it is possible to have this document stand as proof of transfer of the analytical test procedure.

 

Method validation and/or revalidation:-

Another option for accomplishing method transfer is for the receiving laboratory to repeat some or all of the validation experiments. After validation is completed, the second laboratory is deemed qualified to perform the method. The choice of validation parameter(s) depends highly on the type of method being transferred. For example, content uniformity assays to determine consistency of product potency depend heavily on the precision of the method.

 

Method validation and/or revalidation:-

Another option for accomplishing method transfer is for the receiving laboratory to repeat some or all of the validation experiments. After validation is completed, the second laboratory is deemed qualified to perform the method. The choice of validation parameter(s) depends highly on the type of method being transferred. For example, content uniformity/assays to determine consistency of product potency depend heavily on the precision of the method.

 

 

Transfer waiver:-

Certain situations might warrant omitting conventional transfer qualification experiments altogether. When a transfer waiver is applied, the receiving laboratory can proceed to use the analytical test procedures under discussion without generating inter laboratory comparative testing data.

To proceed without generating such data, one must document the reasons why this action was taken. Examples of these reasons were discussed by PhRMA workshop attendees; they include the following:

 

• The receiving laboratory already is testing the product and is thoroughly familiar with the procedure(s).

• The new dosage form possesses either a comparable composition or concentration of active pharmaceutical ingredient relative to the existing product.

• The analytical method(s) are the same or very similar to the methods that are already in use.

• The method validation package encompasses the new methods.

• Personnel who developed the methods move from one site or laboratory to another as the project

• The new methods involve changes that do not substantially alter the ability to use the method (e.g., changes in sample preparation procedures or changes in calculation formulas).

 

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Disclaimer:-This presentation is solely prepared for training, sharing knowledge and information purpose only  collected from various guidelines and literature. The information presented here is only for reference purpose.

 

THANK YOU

Topic– Method Validation

 

Definition:

Validation is a process of establishing documentary evidence demonstrating that a procedure, process or activity carried out in the production or testing maintains the desired level of compliance at all stages.

Analytical method validation is a process of documenting/proving that an analytical method provides analytical data acceptable for the intended use.

 

Guidelines – 1

–-Q2 (R1)-Validation of analytical procedures : Text and Methodology.

–USP <1225>Validation of compendial procedures

–USP <1226>Verification of compendial procedures

* Specificity

* Force Degradation (If Applicable)

* Precision

1. Repeatability

2. Intermediate precision

3. Reproducibility   

*Linearity and Range

*Accuracy

*Robustness

*Limit of detection (LOD) and Limit of Quantitation (LOQ

*Solution stability

 

Specificity:

Ability to asses unequivocally the analyte in the presence of components which may be expected to be present (Impurities, degradants)

For assay and impurity methods the samples shall contain materials which are potentially present during routine analysis and may interfere with the result, e.g. analysis sample containing potential interferences, e.g. impurities, Excipients.

Sample shall prepared by spiking drug substance / drug product with potentially interfering material. The acceptance criteria shall be; No interference observed for response due to analyte or impurities or interest and no peaks interfering with analyte peak or the peaks due to the impurities of interest observed. Peak purity shall not be less than 0.995.

For the impurities test, the determination shall be established by spiking drug substances or drug product with appropriate levels of impurities and demonstration the separation of these impurities individually or from other components in the sample matrix.

 

Forced degradation:-

Forced degradation shall be done in presence of excipients, firstly performed during the pre-formulation stage to assist in the selection of the most formidable compounds and excipients. This shall lead to the development of more suitable formulation, packaging and change in storage and manufacturing conditions as the optimal formulation is defined to be used. Forced degradation studies are also in order to demonstrate specificity during the validation of stability indicating methods.

These studies are usually performed at conditions exceeding that of accelerated storage condition.

Forced degradation studies shall provide information to degradation pathway and degradation products that could form during storage of the drug product.

The extent of targeted degradation shall be approximately anywhere from 5% to 20%. In some cases the degradation can be difficult to achieve 5%, in such cases statement shall be made in the validation report that the product quality / efficacy shall not be affected for such particular stress condition. The assessment of peak purity using diode array shall be employed.

 

Precision:

Precision is the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample. There are following aspects to achieve for precision.

1. Repeatability:

Repeatability is a measure of precision under the same operating conditions over a short interval of time that is, under normal operating conditions of analytical method with the same equipment.

Repeatability to be accessed using a minimum of nine determinations covering the specified range for the procedure (e.g. three concentrations / three replicates as in the accuracy experiment) of using a minimum six determination at 100% of the test concentration. Standard deviation, relative standard deviation and confidence interval to be reported. The assay value of independent analysis of sample preparation to final test result. For the related substances, residual solvents precision shall be established at 100% specification level of know impurities / organic solvents and also to be established at the limit of quantification level.

 

 

b.  Intermediate precision:

Intermediate precision is defined as the variation within the same laboratory. The extent to which intermediate precision needs to be established depends on the circumstances under which the procedure is intended to be used. Typical parameters that are investigated include day to day variation, analyst variation and equipment variation. Depending upon the extent of the study, the use of experimental design is encouraged.

Experimental design shall be minimize the number of experiments that need to be performed. It is from doing intermediate precision when reproducibility is proven. It shall be expected that the intermediate precision shall show variability that is in same range or less than repeatability variation. The standard deviation, relative standard deviation (coefficient variation) and confidence interval to be established of data.

 

c. Reproducibility:

Reproducibility measures the precision between laboratories. This parameter shall be considered in the standardization of an analytical method (e.g. inclusion of procedures in pharmacopoeias and method transfer between different laboratories).

To validate this characteristic, similar study to be performed at different laboratories using the same homogeneous sample lot and the same experimental design. In case of method transfer between two laboratories, different approaches may be taken to achieve the successful transfer of the procedure. The approach is method transfer from the originating laboratory to the receiving laboratory. The originating laboratory is defined as the laboratory that has developed and validated analytical method. The receiving laboratory is defined as laboratory to which the analytical method to be transferred and that will participate in the method transfer studies. In the method transfer, it is recommended that protocol be initiated with details of the experiments to be performed and acceptance criteria (in term of the difference between the means of the two laboratories) for passing the method transfer.

 

 

Linearity:-

Linearity of an analytical procedure as the ability (within the given range) to obtain test results of variable data (e.g. absorbance and area under the curve) which are directly proportional to the concentration (amount of analyte) in the sample. The data variables that shall be used for quantitation of the analyte are the peak area or ration of peak area of analyte to the internal standard peak. The working sample concentration and samples tested for accuracy shall be in the linear range.

There are two general approaches for determining the linearity of the method.

The first approach is to weigh different amounts of standard directly to prepare linearity solutions at different concentrations. However, it is not suitable to prepare solution at very low concentration, as the weighing error shall be relatively high.

Another approach is to prepare a stock solution of high concentration. Linearity is then demonstrated directly by dilution of standard stock solution. This is more popular and the recommended approach.

Linearity is best evaluated by visual inspection of a plot of signals as a function of analyte concentration. Subsequently, the variable data are generally used to calculate a regression line by the least square method. At least five concentration levels shall be used.

Under normal circumstances, linearity shall be with coefficient of determination (r²) of 0.995 the slope, residual sum of squares, and y- intercept shall also be reported.

The slope of the regression line shall provide an idea of the sensitivity of the regression. The y intercept shall provide an estimate of the variability of the method. The ratios percent of the y intercept with the variable data at nominal concentration are used to estimate the method variability.

For determination of assay of drug substances of a drug product, the usual range of linearity shall be ±20% of the target or nominal concentration. For the determination of content uniformity, it shall be ±30% of the target of nominal concentration. For determination of related substances or residual solvents it shall be from the reporting level to 20% ahead of the target or nominal concentration. For dissolution testing: ±20% over the specified range.

Limit of Detection (LOD):-

It is the lowest amount of analyte in a sample that shall be detected but not necessarily quantitated under the stated experimental conditions.

The detection shall usually expressed as the concentration of the analyte in the sample, e.g. percentage, parts per million (ppm) or parts per billion (ppb).

There are several approaches to establish the limit of detection. One approach to establish detection limit shall be determined by the analysis of a series of sample with known concentrations and establishing the minimum level at which analyte shall be reliably detected. For instrumental procedures that exhibit background noise, it shall compare measured signals from samples with known concentrations of analyte with those of the blank samples. The minimum concentration at which the analyte shall reliably be detected, shall establish using an acceptable signal to noise ratio of 2:1 or 3:1.

Presentation of relevant chromatograms shall be sufficient for justification of detection limit.

 

 

Limit of Quantitation (LOQ):-

Quantitation limit is determined by analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte shall be quantitated with acceptable accuracy and precision.

signal to noise ratio by comparing measured signals from samples with known low concentration at which the analyte shall be reliable quantified at the signal to noise ration 10:1.

Accuracy:-

Accuracy of an analytical procedure as the closeness of agreement between the values that are accepted either as conventional true values or an accepted references value and the value found. For the drug substances accuracy is defined by the application of the analytical procedure to an analyte of known purity (e.g. reference standard). For the drug product, accuracy shall be determined by application of the analytical procedure to synthetic mixtures of the drug product components to which amounts of analyte have been added within the range of the procedure. It is recommended to assess minimum of nine determinations over a minimum three concentration levels covering the specified range (e.g. three concentration / three replicates).

Accuracy shall be reported as percent recovery by assay (using the proposed analytical procedure) of known added amount of analyte in the sample of as the difference between the mean and the accepted true value together with the confidence intervals. The range for the accuracy limit shall be within the linear range. Typically accuracy of the recovery of the drug substance is expected to be about 99 – 101%.

Typical accuracy of drug product is expected to be 98 – 102%. For the dissolution of drug product accuracy of recovery is expected to be 98 – 102%. Values of accuracy of recovery data beyond this range need to be investigated as appropriate.

For the related substances / residual solvents recovery shall be performed from the quantitation limit by spiking the known concentration of known impurities / residual solvents in analyte and the accuracy of recovery can be up to 85 – 115%.

For Cleaning validation recovery shall be performed from the quantitation limit to minimum 120% by spiking the known concentration of known analyte and the accuracy of recovery should not be less than 70%.

 

Robustness:-

Robustness of an analytical procedure is a measure of the analytical method to remain unaffected by small but deliberate variations in method parameter and provides an indication of its reliability during normal usage.

Common method parameters that can affect the analytical procedure shall be considered based on the analytical technique;

Sample preparation

Extraction time

High performance liquid chromatography (HPLC) conditions;

Mobile phase composition (pH ±0.05, percent organic ± 2% absolute) Column used (equivalent columns, lots and / or suppliers) Temperature (± 5º C)

Flow rate (± 10 %)

Gas chromatography (GC) conditions

Column used (equivalent columns, lots and / or suppliers) Temperature (± 10 %)

Flow rate (± 10 %)

When the results are affected by some critical experimental parameters, a precautionary statement shall be included in the analytical procedure to ensure that this parameter is tightly controlled between experiments. For example: in case percent ion pairing of mobile phase affects the results significantly, the analytical procedure shall explicitly be written with a precautionary statement for aqueous component.

 

Solution stability:-

Stability of Standard and Sample Solution shall be performed at various time intervals and at room temperature.

Acceptance criteria shall be as follows :

For assay and dissolution, the relative standard deviation for peak area as obtained from standard solution and test solution shall not be more than 2.0%.

For related substance and residual solvents, the relative standard deviation for peak area as obtained from standard solution and test solution shall not be more than 10.0 % at various time intervals.

Method Verification:-

Verification consists of assessing selected analytical validation characteristics described earlier to generate appropriate relevant data rather than repeating the validation process for commercial products. The method verification shall be done for the pharmacopeial methods (compendial methods) such as titrations, chromatographic procedures (related compounds, assay, dissolution and limit tests), and spectroscopic tests.

However, general tests (water, heavy metals, residue on ignition) do not typically require verification.

Range:-

The range of analytical procedure is the interval between the upper and lower concentration of analyte in the sample for which it has been demonstrated that the analytical procedure shall a suitable level of precision, accuracy, and linearity. The range shall normally expressed in the same units as test results (e.g. percent, parts per million) obtained by the analytical procedure.

 

 

Method Revalidation:-

The analytical method shall be revalidation under following circumstances; however these circumstances are not limited;

In case new impurity found that makes deficient in its specificity, this method needs to be modified and revalidated.

Changes in the excipients composition can change the product impurity profile.

Changes in equipment or supplier of critical supplies of the API (Active Pharmaceutical Ingredients) or final drug product shall have the potential to change their degradation profile and shall require the method to be redeveloped and revalidated.

 

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Disclaimer:-This presentation is solely prepared for training, sharing knowledge and information purpose only  collected from various guidelines and literature. The information presented here is only for reference purpose.

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Topic:-Stability Studies (2) – an overview

• Stability: Fundamentals :-

The ability of a pharmaceutical product to retain its properties within specified limits throughout its shelf life. Aspects of stability that are to be considered include: Physical, Chemical, Microbiological & Biopharmaceuticals.

 

“It is It is a study on the evidence on how the quality of a drug substance or drug products varies with time under the influence of variety of environmental factors such as Temperature, Humidity and Light.”

 

• Objective – why stability

• To provide evidence on how the quality of a drug substance / product varies with the influence of variety of environmental factors such as temperature, humidity & light

• To recommend storage conditions

• To recommend retest period

• To assign shelf life

• To review the product quality

• To fulfill the regulatory requirement for dossier submission

• Why is stability testing an important issue ?

• In order to demonstrate that:

  • the clinical effect

  • the patient safety

  • the quality

  • of the drug is maintained during its maximal time of storage and intended use.

Starting a Study :-

Contents of a stability protocol

Setting the ‘start date’ for a stability study

Determining the ‘due dates’ for a stability study protocol The initial certificate of analysis at to for a stability study SOP Control

Format and layout of standard operating procedures Indexing procedure for stability studies

Index for stability sops

Study Parameters

Setting limits for check specifications in a stability study. Number and size of batches for stability testing.

Sampling

Number of samples required for performing stability tests Labeling of stability study samples

Storage configuration of samples in a stability environment

Storing the stability study samples under controlled conditions prior to analysis

Study Conditions

Intervals and climatic conditions for a development stability study Intervals and climatic conditions for a pivotal/bioequivalence stability study

Intervals and climatic conditions for a validation/pm stability study Placing the reference listed drug (RLB) on stability

Packaging procedures

Sampling and testing of pivotal batches – tablet & capsule dosage forms. Sampling and testing of pivotal batches – powder & syrups for reconstitution.

Container systems

Container-liner-closure systems for a stability study.

Certification of a container-liner-closure system.

Test methods

The control of analytical methods and  stability documentation

 

Test results

Reporting test results of a stability study.

Procedures for handling abnormal or OOS results in a stability study.

Audit and Review Raw Data

Auditing stability data in laboratory notebooks

Cross-referencing laboratory notebooks with computerized stability documentation

Chart Control

Recording stability study climatic conditions

Review and control of temperature and humidity recording charts

Validation and Sanitation

Periodic revalidation of climatic rooms and chambers

Sanitation and housekeeping requirements of climatic chambers

Corrective Action

Fault correcting procedures (after breakdowns) during a Stability Study Emergency procedures during a stability study

 

Stopping a Study

Conditions for stopping a stability study.

Self Inspection

Self inspection procedures in a stability department.

Job Description and Training

Job description of stability department personnel

Using stability SOPs and compliance program as stability training tools. The Do’s and Don’ts of a stability study – a department training tool.

Stability department compliance staff training

Reviewing Documentation

Review and auditing stability study documentation.

The layout and format of a regulatory stability report (a filed report)

Documentation requirements for a stability study – contents of a stability dossier

Closing a Study

Accepting and signing-off a completed stability study.

 

Stability protocol – contents:

 * Name of the product

• Batch size, type of batch and number of batches

• Source of API

• Type, size, source of containers and closures

• Storage condition

• Sampling schedule

• Container storage orientation

• Test parameters

• Test methods

• Acceptance criteria

 

• Stages of stability :

  • Pre-formulation / pre-experimental

  • Formulation / experimental stability

  • Pilot / post experimental stability

  • Production / commercial stability

Stability studies during product life-cycle

Development——> Submission and Approval—–> Post-approval

Development	Submission and Approval	Post-approval
•   Stress testing •   Photostability •  Studies to support process & product development •Clinical trial stability •  Shipping and In-use stability •Intermediates	•Formal studies for the application	•Commitment batches • Follow-up stability program • Stability studies initiated by: –   Changes –   Deviations

Guidelines for Stability Testing:

• ICH guidelines on Stability testing of new drug substances and drug   products

• USFDA guidelines on Stability testing

• CPMP guidelines on stability

• WHO guidelines on stability testing of pharmaceutical products

Global climatic zones:

 

Region	Zones I & II	Zones III & IV
European	All countries	–
American	Chile, Canada, United States	Brazil, Jamaica, Venezuela
Asian	China, Japan, Turkey	India, Philippines, Sri Lanka
African	South Africa, Zambia, Zimbabwe	Botswana, Ghana, Uganda
Australian / Oceanic	Australia, New Zealand	Fiji, Papua – New Guinea

 

Q1A : Stability Testing of New Drug Substances & Products.

Q1B : Stability Testing : Photostability testing of New Drug Substances & Products.

Q1C : Stability Testing for New Dosage Forms.

Q1D : Bracketing & Matrixing Designs for Stability Testing of Drug Substances & Products.

Q1E : Evaluation of Stability Data.

 

Q3A : Impurities in New Drug Substances.

Q3B : Impurities in New Drug Products.

Q3C : Impurities: Guideline for Residual Solvents.

Q3C(M): Impurities: Guideline for Residual Solvents (Maintenance).

 

Specifications :

• List of Tests

• Testing procedure

• Acceptance criteria (at the time of release / shelf life).

• Reference standard

• In-process tests

• Physical tests such as particle size distribution

• Parametric releases

• Various decision trees

• Impurities

• Micro Limits

 

The testing should cover as appropriate : chemical, physical, biological & microbiological parameters. Validated analytical method should be adopted.

 

• Stability Specification

• Product relase specifications: ”…include those attributes of the drug product/drug substance that are susceptible to change during storage and likely to influence quality, safety and/or efficacy”

  End shelf life ( Stability) specification The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated”

 

• Stability Testing Frequency

• Long Term :

• First year     : Every 3 Months

• Second year : Every 6 months.

•  Thereafter    : Annually.

• Intermediate : 0, 3, 6, 9, 12 (Months)

• Accelerated : 0, 3, 6 (Months)

Storage Condition :  General case:

Study	Storage condition	Minimum time period covered by data at submission
Long Term	25 ± 20C / 60 ± 5% RH	12 months
Intermediate	30 ± 20C / 65 ± 5% RH	6 months
Accelerated	40 ± 20C / 75 ± 5% RH	6 months

Any “significant change” occurs during 6 month accelerated study, additional testing at intermediate storage should be conducted. The initial application should include a minimum of 6 moths data from 12 month study of intermediate storage condition.

“Significant change” for a drug substance is failure to meet specification. For drug product, it is given separately.

Storage Condition :

Drug Substance / Drug Product intended for storage in refrigerator :

Study	Storage condition	Minimum time period covered by data at submission
Long Term	5 ± 3°C	12 months
Accelerated	25 ± 2°C / 60 ± 5% RH	6 months

If   “significant  change”   occurs   between   3   &   6     months  of accelerated study, data on long term study should be submitted.

If “significant change” occurs within 3 months of accelerated study, it is unnecessary to continue further testing.

• Storage Condition Drug Substance / Drug Product intended for storage in freezer :

 

Study	Storage condition	Minimum time period covered by data at submission
Long Term	– 20 ± 5°C	12 months

 

There is no accelerated study for above case.

Drug substance intended for storage below – 20°C should be treated case by case.

 

 

Ø COMMITMENT

• Initial long-term data on primary batches may not cover the proposed shelf life granted at the time of approval.

• Commitment is made to continue the post approval studies in order to firmly establish the shelf life.

• If the submission includes data from studies on less than 3 production batches, a commitment is made to continue the long term studies during the proposed shelf life and place additional production batches to make a total of at least 3 on long-term studies through the proposed shelf life.

• If the submission does not include stability data on production batches, a commitment should be made to place the first 3 production batches on long term studies during the proposed shelf life and accelerated studies for 6 months.

 

EVALUATION OF STABILITY DATA TO ESTABLISH SHELF LIFE – For Drug Products RE-TEST DATE – For Drug Substances

If accelerated stability data for 6 months is OK.

 

	x	y
Accelerated (6months)	Long Term  (9 months OK)	y = 2x Shelf life / re-test date is 18 months
Accelerated (6months)	Long Term (12 months OK)	y = 2x Shelf life / re-test date is 24 months
Accelerated (6months)	Long Term (18 months OK)	y = x + 12 Shelf life / re-test date is 30 months
Accelerated (6months)	Long Term (24 months OK)	y = x + 12 Shelf life / re-test date is 36 months
Accelerated (6months)	Long Term (36 months OK)	y = x No extrapolation beyond 36 months

 

 

EVALUATION OF STABILITY DATA TO ESTABLISH SHELF LIFE For Drug Products RE-TEST DATE For Drug Substances

If accelerated stability data for 6 months is NOT OK.

	x	y
Accelerated (6months)	Intermediate 12 months OK	y = 1.5x Shelf life / re-test date is 18 months
Accelerated (6months)	Intermediate 9 months OK	y = 1.5x Shelf life / re-test date is 13.5 months
Accelerated (6months)	Intermediate 9 months NOT OK & if long term 9 months OK	y = x + 3 Shelf life / re-test date is 12 months

STABILITY DATA EVALUATION 

  

• Consider assay, degradation products & other appropriate attributes for evaluation of stability study data.

• Use formal   statistical  analysis   for   data showing substantial variability & degradation.

• Do not apply this statistical analysis for stability data showing little degradation / variability.

• The nature of degradation relationship determines whether it should be converted for linear regression analysis.

SIGNIFICANT CHANGE

 

What does significant change means… For Drug Substance : Failing to meet its specification. For Drug Products :

• 5% assay variation from its initial

• Failure to meet the acceptance criteria for potency when using biological / immunological procedures.

• Any degradation products exceeding acceptance

• Failure to meet acceptance criteria with respect to :

  • Appearance l Color l Phase separation

  • Re-suspendibility l Caking l Hardness

  • pH l Dissolution on 12 units

Some acceptable factors such as softening of suppositories & melting of creams may be accepted at accelerated conditions.

 

 

 

LABLELING CONSIDERATION FOR

DRUG PRODUCTS & DRUG SUBSTANCES

Statement / Labeling :

• A storage statement should be based on the stability evaluation. Wherever applicable, specific instructions should be provided. For eg.: drug substances that cannot tolerate freezing.

• Avoid use of “ambient condition” or “Room temperature”.

• Need direct   link   between   the   label   storage           statement    &             the

demonstrated stability.

• A retest period for drug substance & expiration for the drug product should be derived from stability information, and should be displayed on the container label as appropriate.

LABLELING CONSIDERATION FOR DRUG PRODUCTS & DRUG SUBSTANCES

	Testing conditions where stability has been shown	Required labeling statement	Additional labeling statement, where relevant
	25 ± 20C / 60 ± 5% RH (long term) 40 ± 20C / 75 ± 5% RH (accelerated) or 30 ± 20C / 65 ± 5% RH (long term) 40 ± 20C / 75 ± 5% RH (accelerated)	None	Do not refrigerate or freeze.
	25 ± 20C / 60 ± 5% RH (long term) 30 ± 20C / 65 ± 5% RH (intermediate) or 30 ± 20C / 65 ± 5% RH (long term)	Do not store above 30 0C or Store below 30 0C.	Do not refrigerate or freeze.
	25 ± 20C / 60 ± 5% RH (long term)	Do not store above 25 0C or Store below 25 0C.	Do not refrigerate or freeze.
	5 ± 30C (long term)	Store in a refrigerator or Store & transport refrigerated.	Do not freeze.
	Below zero	Store in a freezer or Store & transport frozen	—

 

OTHER SPECIFIC STORAGE STATEMENTS

 

Sr. No	Storage problem	Additional labeling statements* depending on the packaging
1.	Sensitivity to moisture.	Keep the container*** tightly closed.
2.	Sensitivity to moisture.	Store in the original package.
3.	Sensitivity to light.**	Store in the original package.
4.	Sensitivity to light.**	Keep the container*** in the outer carton.

*An :explanation for the labeling statement should be given in the package leaflet (e.g. “in order to protect from light”) and on the outer packaging, where space permits.

 

BRACKETING ICH REFERENCE: Q1D

OBJECTIVE

To provide guidance on application of Bracketing and Matrixing for stability studies of Drug product and Drug substance.

 

What is Bracketing ?

Bracketing is the design of stability schedule such that only samples of extremes of certain design factors (strength / container size & / or fill) are tested at all points a sin full design. The design assumes that the stability of any immediate levels is represented by the stability of extremes tested.

The case of bracketing design would be considered appropriate if design factors selected for testing are indeed the extremes.

BRACKETING Design Consideration and Potential risk:

If the stability of the extremes is not satisfactory, the intermediate should be considered NO more stable than the extremes.

 BRACKETING Where it can be applied:

1. Capsules / tablets of different strengths, manufactured using the same granules / powder (linear formulation) varying in different quantity.

Examples :

Strength               Powder fill / wt. of tab.

10 mg      =     100 mg

20 mg      =     200 mg

50 mg      =     500 mg

II.   When the container size & fill volume vary. However, care should be taken to select the extremes by comparing the various characteristics of the container & closure system that may affect the product stability, such as –

• Composition of container

• Wall thickness

• Head space to volume ratio

• Water vapor penetration rate,

III. BRACKETING – REDUCED DESIGN STUDY

 Example 2 :

Tablet range made with different compression weights of linear formulae.

Strength/tab.

25 mg

50 mg

100 mg

200 mg

Batch No.

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

Container Size

100 s

ü

ü

ü

X

X

X

X

X

X

ü

ü

ü

250 s

X

X

X

X

X

X

X

X

X

X

X

X

500 s

ü

ü

ü

X

X

X

X

X

X

ü

ü

ü

ü : Data required (test to be performed)

X

Bracketing (test not necessary)

 

 

WHAT IS MATRIXING ?

1. It is a stability schedule

2. It is a selection of subset of the total number of samples.

3. It assumes all factor combinations tested at a specified time point.

4. The various factor combination to be considered:

Ø Different batches.

Ø Different strengths.

Ø Different sizes of same containers.

Ø Different closure system.

•   MATRIXING

When a secondary packing system contributes to the stability the drug product matrixing can be performed across the packing system.

Design factors to be considered for Matrixing:

1. Strength of the dosage

2. Container size

3. Container fill.

In a matrix approach, a supporting data with respect to the effect due to:

• Moisture

• Light

• Oxygen

is required to prepare a design close to the ideal one.

Matrixing has a limited use in stability testing of Drug substance but it will have significant applicability in drug products depending on strength, container, closure fill volume, supporting data etc.

 

BRACKETING v/s. MATRIXING

• Bracketing and Matrixing is compliment to each other. Both the techniques helps to reduce the design of various combination factors based on strength, containers/ closures, fills and point of testing time.

• Both Matrixing and Bracketing is a reduced design on different principles.

• The use of Bracketing and Matrixing is generally applied together.

• The design should be scientifically justified.

• BRACKETING IS GENERALLY NOT APPLICABLE TO DRUG SUBSTANCE

• Bracketing is  applicable  to  Drug  product  based  on  different strengths, containers, closures and fill volumes.

Ø CONCLUSION

• Bracketing & Matrixing is a stability schedule & a reduced design. The number of test to be performed on a different size, pack & strength should be logically justified to reduce the analytical load. Bracketing and Matrixing is more applicable for drug

 

 

IMPURITIES IN NEW DRUG SUBSTANCES

Classification of impurities:

1. Organic impurities (Process & Drug related).

2. Inorganic impurities

3. Residual Solvents

 

Identification Threshold:

A limit above which an impurity should be identified.

Qualification Threshold:

A limit above which an impurity should be qualified. Qualification is the process of acquiring and evaluating data that establishes biological safety of individual impurity level specified. The level of any impurity present in a new drug substance that has been adequately tested in safety and / or clinical studies would be considered qualified.

 

IMPURITIES IN NEW DRUG SUBSTANCES

Thresholds: (Drug substances)

Maximum daily dose (1)	Reporting Threshold(2,3)	Identification Threshold (3)	Qualification Threshold (3)
< 2 gram per day	0.05%	0.1% or 1 mg per day intake ( whichever is low)	0.15% or 1.0 mg per day intake (whichever is low)
>2 gram per day	0.03%	0.05%	0.05%

 

1. The amount of the drug administered per

2. Higher reporting threshold should be scientifically

3. Lower threshold can be appropriate if the impurity is unusually toxic.

 

 

CONCLUSION

• Reporting, identifying & qualifying of impurities are based on the total daily intake & the same has been detailed in the ICH guideline.

•  WHAT IS A SUPAC GUIDANCE?

 

• A communication that represents the best scientific judgement of the Agency at this time regarding certain scale-up and post- approval issues:

• TYPES OF SUPAC CHANGES

1. Components and Composition

2. Site Changes

3. Batch Size (Scale-Up/Scale-Down)

4. Manufacturing (Equipment/Process)

• Level I changes:

Which are unlikely to have any detectable impact on formulation quality and performance.

• Level II changes:

Which may have significant impact on formulation quality and performance.

• Level III changes:

Which have a significant impact on formulation quality and performance.

SUPAC – Components and Composition changes:

  

Level	Classification	Documentation	Supplemen t
I	·        Complete or partial deletion of colour / flavour ·        Change of excipient ranges upto 5 %	1st production batch on LTSS	AR
II	·        Change in technical grade or specification of excipient ·        Change of excipient ranges upto 10%	1 batch with 3 month Acc data and LTSS data on 1st production batch	PAS
III	·        Change of excipient ranges exceeding 10 %	3 batches with 3 months Acc data and LTSS data on 1st 3 production batches	PAS

 

SUPAC – Site changes:

 

Level	Classification	Documentation	Supplem ent
I	·      Same facility ·      Common personnel	1st production batch on LTSS (optional, but recommended)	AR
II	·      Same contiguous campus Common personnel	LTSS data on 1st production batch	CBE
III	·      Different campus ·      Different personnel	3 batches with 3 months Acc data and LTSS data on 1st 3 production batches	CBE

 

SUPAC – Batch size changes:

 

Level	Classification	Documentation	Supple ment
I	·        Scale up of biobatch / pivotal clinical batch (less than 10 X)	1st production batch on LTSS	AR
II	·        Scale up of biobatch / pivotal clinical batch (More than 10 X)	1 batch with 3 month Acc data and LTSS data on 1st production batch	CBE

 

SUPAC – manufacturing equipment changes:

Level	Classification	Documentation	Supple ment
I	·        Equipment changes (same operating principle)	1st production batch on LTSS	AR
II	·        Equipment changes (different operating principle)	3 batch with 3 month Acc data and LTSS data on 1st 3 production batch	PAS

 

SUPAC – Manufacturing process changes:

 

Level	Classification	Documentation	Supple ment
I	·      Adjustment within operating conditions (e.g. Mixing time, speed with in validated range)	1st production batch on LTSS (Optional, recommended)	AR
II	·      Adjustments outside operating conditions (outside the validated range)	LTSS data on 1st production batch	CBE
III	·      Change of process (e.g. Wet granulation to direct compression)	3 batches with 3 months Acc data and LTSS data on 1st 3 production batches	PAS

 

Photo stability – Light source:

• Option 1: Artificial daylight fluorescent lamp combining visible and UV outputs, xenon or metal halide lamp. or

• Option 2: A cool white fluorescent lamp & a near UV fluorescent lamp having a spectral emission range from 320 nm to 400 nm

Level of exposure for stability study:

• Overall illumination of not less than 2 million lux hours and an integrated near UV energy of not less than 200 watt hours/m2. This can be monitored by either Quinine actinometry, calibrated radiometers or lux meters.

• To exclude the thermal effect, a protected control sample (wrapped in aluminum foil) may be exposed side by side.

 

1. Scientific and Regulatory Aspects

• Importance of preparing and training personnel
• Significance of studies conducted
• Definition of shelf life, expiration dating, developmental, and marketed product stability
• Determination of the storage conditions stability
• Definition of the roles of temperature, humidity, and light
• Key elements of stability testing

 

• 2. Stability Storage Chambers: Calibration, Monitoring, and Maintenance

• Stability chambers and rooms used in the industry

• Installation, Operation, and Performance Qualifications

• Principles of calibration frequency and documentation

• Principles of monitoring frequency and documentation

• Maintenance of stability chambers

3. Stability Storage and Testing as Defined in cGMPs, ICH, and FDA Guidelines

• CGMP requirements for stability storage and testing.

• ICH stability guidelines’ expectations.

• FDA guidelines’ expectations.

• Photo stability studies.

• Forced degradation (stress) and stability-indicating methods.

 

 

 

THANK YOU

Topic:– Stability Studies (1)- an Introduction

 

Definition:

“…… to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity & light, & enables recommended storage conditions, re-test periods & shelf lives to be established.”

 

ICH stability guidelines – 1

Q1A(R2)-Stability Testing of New Drug Substances & Products

Q1B- Stability Testing : Photostability Testing of New Drug Substances & Products

Q1C- Stability Testing for New Dosage Forms

Q1D- Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Q1E- Evaluation of Stability Data

Note that these have been adopted in the European Union, the United States, and Japan

-Accelerated testing

-Studies designed to increase the rate of chemical degradation or physical change by means of exaggerated storage conditions

-Intermediate testing

-Studies at 30°C/65%RH, intended for extrapolation to long term storage at

25°C [provided that 25°C is appropriate for the market in question]

-Stress testing

-API: Studies which elucidate intrinsic stability of API. Normally during development.

Normally more stressful than ‘accelerated’ testing.

-Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture- permeable containers.

 

• Climatic zones:

–Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dry

–Zones (Futscher & Schumacher 1972):

• I Temperate (21^oC/45%RH)

• II Subtropical (25^oC/60%RH with possibly high RH)

• III Hot & dry (30^oC/35%RH)

• IV Hot & wet (30^oC/70%RH)

–The temperatures above are kinetic averages

 

“The Secretariat reminded the Committee that the WHO guidelines had been revised in the light of harmonization efforts in collaboration with ICH. Subsequently focus had been placed within regional harmonization initiatives on the recommendations for hot and humid conditions (referred to as Zone IV). After extensive discussion the Committee reached consensus that the WHO stability guidelines be amended to reflect conditions for Zone IV as follows:

• Zone IVa (30 degrees Celsius and 65% RH); and

• Zone IVb (30 degrees Celsius and 75% RH).

It was agreed that each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb.”

 

• Countries:-

• I – USA, Canada, Northern Europe, Russia.

• II- USA, Southern Europe, Australia, China, Korea, japan, Mexico, South Africa, Turkey.

• III- Iraq, Jordan, Morocco, Sudan, Lybia, Egypt, India.

• IV- Sudan, Taiwan.

• IVa- Bangladesh, Bahrain, Congo, Ethopia, Hong kong, Kuwait, Qatar, Saudi Arabia, Somalia, Sri Lanka, UAE.

• IVb- India, Columbia, Cuba, Ghana, Malaysia, Nigeria, Philippines, Singapore, Thailand.

 

 

 

Each nation within zone IV must now

decide whether to adopt a stability test condition of 30^oC & 65%RH, or 30^oC & 75%RH

ASEAN nations & Brazil have adopted 30^oC & 75%RH

 

 

Reduced study Designs:

-Bracketing :-

-A design in which only the extremes are tested at all time points, eg strength, pack size, container fill etc.

-Matrixing –

-Designs in which a selected subset of samples is tested, eg different strengths, container/closure systems, batches

General case

Study	Storage condition	Minimum time period covered by data at submission
Long term	25oC ±2oC/60%RH ±5%RH or 30oC ±2oC/65%RH ±5%RH	12 months
Intermediate	30oC ±2oC/65%RH ±5%RH	6 months
Accelerated	40oC ±2oC/75%RH ±5%RH	6 months

 

ICH:    “It is up to the applicant to decide whether long term stability studies are performed at 25^oC ±2^oC/60%RH ±5%RH or 30^oC ±2^oC/65%RH ±5%RH.”

 

PQP:   “Unless otherwise justified, 30^oC ±2^oC/65%RH ±5%RH is the real-time condition for the prequalification project.”

And: The minimum time period for intermediate storage is 12 months.

 

“the frequency of testing in the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, & annually thereafter throughout the proposed shelf life.

Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets:

• appearance          ♦         hardness

• friability                ♦         moisture content

• dissolution time ♦         degradants

• assay                     ♦         microbial purity

 

Significant Change;-

• A 5% change in assay from its initial value.

• Any degradation product exceeding its acceptance criterion.

• Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, hardness).

• As appropriate for the dosage form, g., failure to meet the acceptance criteria for dissolution for 12 dosage units.

Commitment:-

For confirmation of provisional (tentative) shelf-life, real-time data are required;

* First 3 production batches on stability.

* Follow up stability testing (FUST) – one batch per year Variations affecting one or more steps of the same route of synthesis of an API.

* Change in the route of synthesis of an API Change in composition of the FPP.

* Change in immediate packaging of the FPP.

 

Evaluation:-

1. Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately.

2. No significant change at accelerated conditions within six (6) months.

3. Long-term data show little or no variability and little or no change over time.

4. Accelerated data show little or no variability and little or no change over time.

5. Statistical analysis is normally.

6. Proposed retest period or shelf life = double of period covered by long-tem data (X) but NMT X + 12 months.

7. A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long- term stability data.

 

 

---

Disclaimer:-This presentation is solely prepared for training, sharing knowledge and information purpose only  collected from various guidelines and literature. The information presented here is only for reference purpose.

 

 

 

THANK YOU

Topic:- Change Control, Deviation & Incident Management

 

1. Change Control

Definition: Change control is the process of managing any alterations or modifications to a project, system, or process in a controlled and systematic way. This ensures that any change is reviewed, documented, and approved before being implemented, preventing unintended consequences or disruptions.

2. Deviation

Definition: A deviation refers to a departure from an established standard, process, or procedure. This can occur when something does not meet the specified requirements, whether due to human error, equipment failure, or external factors. It requires investigation and corrective action.

3. Incident

Definition: An incident is an event or occurrence that disrupts normal operations, processes, or systems. A discrepancy in implementation of GMP or failure of systems in day-to-day operation. It typically requires a response to resolve and mitigate the impact.

 

	Change Control	Deviation	Incident
	Change includes any Addition to, Deletion of or Modification	A departure from standard practices or Procedures	A discrepancy in implementation of GMP or failure of systems in day-to-day operation
	Critical, Major, Minor	Planned/Unplanned Critical, Major, Minor	Critical, Major, Minor
	User/concern department should initiate	User/concern department should initiate	User/concern department should initiate
	All supporting and reference documents shall be attached to the form	All supporting and reference documents shall be attached to the form	All supporting and reference documents shall be attached to the form

	Change Control	Deviation	Incident
	Justification shall be provided by initiating department	The supervisor shall perform initial investigation to find out cause	The supervisor shall perform initial investigation to find out cause
	form and supporting document shall be reviewed for its appropriateness by HOD	form and supporting document shall be reviewed for its appropriateness by HOD	form and supporting document shall be reviewed for its appropriateness by HOD
	QA shall done primary evaluation and allot number	QA shall done primary evaluation and allot number	QA shall done primary evaluation and allot number
	form shall be circulated to Concerned Department for impact assessment and comments	form shall be circulated to Concerned Department for impact assessment of CAPA	form shall be circulated to Concerned Department for impact assessment of CAPA

 

	Change Control	Deviation	Incident
	QA shall review all comments to assess any other impact of the change	QA shall review all comments to assess any other impact of the deviation	QA shall review all comments to assess any other impact of the incident
	After complete assessment, change shall be approved or rejected	Deviation shall be authorize by QA	Root cause shall be investigated
	Implementation and follow up shall be done by Initiating and QA department	Implementation and follow up shall be done by Initiating and QA department	Implementation and follow up shall be done by Initiating and QA department
	shall be closed within 30 days from the date of initiation	shall be 30 working days from the date of incident filing	shall be closed within 30 days from the date of initiation

 

Change Control	Deviation	Incident
The appropriateness and effectiveness of the action taken shall be evaluated and verified after implementation	The appropriateness and effectiveness of the action taken shall be evaluated and verified after implementation	The appropriateness and effectiveness of the action taken shall be evaluated and verified after implementation
Final review of the completed deviation report shall be done and comment shall be made with closeout date	Final review of the completed deviation report shall be done and comment shall be made with closeout date	Final review of the completed deviation report shall be done and comment shall be made with closeout date

Disclaimer:-This presentation is solely prepared for training, sharing knowledge and information purpose only  collected from various guidelines and literature. The information presented here is only for reference purpose.

 

 

 

THANK YOU

TOPIC:- GOOD DOCUMENTATION PRACTICES

 

Good Documentation Practice:

It is an important part of Good Manufacturing Practice which specifies the standard of document completion should meet the minimum requirements based on regulatory guidelines, requirements and expectations. It is the responsibility of all employees to follow Good Documentation Practice.

 

 

Principles of Good Documentation Practice:

–A document bearing original signatures should never be destroyed.

–Never falsify information.

–Never use a White-out and cover-over-tapes.

–Never obliterate information or record.

–Never over-write a record.

–Never use pencil – all information should be completed in permanent Blue ink.

–No spaces, lines or fields are to be left blank.

–Never use symbols e.g. ditto marks or arrows to indicate repetitive and consecutive.

 

Different Types of Documents and Records:

–BMR /BPR , BOMs, Specifications, SOP, Protocols, Policies, Test Methods, Forms/Log sheets, Quality records , CoA, Technical transfer reports, Validation documentation, Training Assessments.

General Requirements for Good Documentation Practices:

1. All documents must be clear, accurate and written in a manner that prevents errors and ensures consistency.

2. All records must be filled out in indelible blue ink ball point pen for long term Do not use pencil or ink that can be erased.

3. Documents and records should be reviewed by someone who did not perform the task to ensure that the information is correct and accurate.

4. Handwritten signatures must be unique to the individual and listed within the site signature specimen list

5. GMP records are accurate and any changes or amendments are made in a compliant manner.

6. Deliberately amending or destroying GMP records to hide or falsify data is fraud.

7. Do not discard a GMP record just because you might have made a mistake, it is still required for traceability.

8. It is not acceptable to discard GMP records for any reason unless the retention period expiry is reached.

9. Loose unofficial papers, notes and uncontrolled documents that can easily be lost or changed without appropriate approval do not meet GDP requirements.

10. Do not use notebooks/legal pads with easily removed pages, scrap paper or post-it-notes to record GMP information.

11. blank spaces, rows, columns must be marked out NA with a single line across the whole field or

12. Back dating of entries is not permitted

 

13. Making legible correction–Make a single line through the error Record the correction close by with sign and Date of correction. Numbering corrections is acceptable when space is limited. If the record becomes too congested with corrections, an attachment may be used, however the original record must indicate the number of pages attached and the attachment reference the record it is related to.

14. Date Format:

DD/MM/YY e.g.: 01/01/24

15. Time Format:

HH:MM (24 Hrs) e.g.: 13:17

What is ALCOA?

 

It gives idea about how data should be recorded, handled, and retained to comply with regulations such as FDA 21 CFR Part 11, EU GMP Annex 11, and ICH Q7/Q9/Q10.

 

ALCOA is an acronym that stands for:

1. Attributable

2. Legible

3. Contemporaneous

4. Original

5. Accurate

Detailed Explanation of ALCOA Principles

Attributable :-	Every data entry should clearly show who performed the action and when. This includes time stamps and user identification (e.g., a login ID or signature).
Legible :-	All data must be readable and understandable. If handwritten, it must be clear; if electronic, it must be in a format that is accessible and preserved for the required retention period.
Contemporaneous:-	Data must be recorded at the time the activity is performed, not afterward. This ensures accuracy and traceability.
Original :-	The record should be the first capture of the data (e.g., a signed form, electronic log, or validated electronic record). If copies are used, they must be verified as true copies.
Accurate :-	Data should be free from errors, with proper corrections made transparently. Any modification must be documented without obscuring the original entry.

 

What is ALCOA++?

ALCOA++ builds on ALCOA by including additional principles that further enhance data quality and compliance. The “++” elements focus more on data integrity culture and the management system around data.

Complete:-

All data must be entire, meaning nothing relevant has been deleted, omitted, or hidden. Includes metadata, audit trails, and all associated records.

Consistent:-

Data entries should be in a logical sequence and follow procedures, using consistent formats, timestamps, and standards.

Enduring:-

Records must be preserved in a durable format for the required retention period. Fragile formats (e.g., post-it notes) are not acceptable.

Available:-

Data must be accessible for review and inspection throughout its lifecycle. It should be retrievable when needed, even years after creation.

 

THANK YOU

TOPIC- DISSOLUTION

Definition:

Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase.

Dissolution is the rate determining step for hydrophobic,

poorly aqueous soluble drugs.

Why dissolution studies?

1. To show that the release of drug from the tablet is close to 100%.

2. To show that the rate of drug release is uniform batch to batch.

3. And to show that release is equivalent to those batches proven to be bioavailable and clinically effective.

Apparatus Classification in USP:

1. Apparatus 1 (rotating basket)

2. Apparatus 2 (paddle assembly)

3. Apparatus 3 (reciprocating cylinder)

4. Apparatus 4 (flow-through cell)

5. Apparatus 5 (paddle over disk)

6. Apparatus 6 (cylinder)

7. Apparatus 7 (reciprocating holder)

A drug product is considered rapidly dissolving when;

no less than 85% of the labeled amount of the drug substance dissolves within 30 minutes, using USP Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media:

• 1 N HCl or Simulated Gastric Fluid USP without enzymes;

• a pH 5 buffer; and

• a pH 8 buffer.

 

Biopharmaceutical Classification System;

Class I:

High solubility—High permeability

Class II:

Low solubility—High permeability

Class III:

High solubility—Low permeability

Class IV:

Low solubility—Low permeability

Why Qualification & Validation of the Apparatus?

-To maintain “quality by design”.

-Physical & chemical calibrations—for geometrical & dimensional accuracy & precision.

-Vibration or undesired agitation to be avoided.

-Temperature, rotation speed/flow rate, volume, sampling probe, procedures, etc. need to be monitored periodically.

Use of USP calibrator tablets for App. 1 & 2 (to be performed not less than twice a year)

Solubility of solid in dissolution medium;

• Temperature of dissolution medium.

• pH of the medium.

• Solubility of the drug in dissolution medium.

• Presence of co-solvents.

Dissolution rate constant

Depend upon;

• Thickness of boundary layer

• Degree of agitation

• Speed of stirring

• Shape, size & position of stirrer

• volume of dissolution medium

• Shape & size of container

• Viscosity of dissolution medium

• Dissolution Acceptance Criteria in case of Failure;

• 

THANK YOU

TOPIC:– TRAINING TO THE EMPLOYEES

Training:

Training is defined as a process of teaching or learning a skill through interaction.

On-the-Job Training: is a form of training taking place in a normal working situation in their respective areas of operation according to the training need identification of individual departments.

Aim to develop the knowledge, skills and attitude necessary for effective performance of the work.

Reason for training :-

• New technology.

• Updation of skills.

• Cost control.

• Globalization and speed of change.

• Designing of training :-

• Who are the trainees.

• What methods and techniques.

• What should be the level of training.

• Implementation of training program :-

.deciding the location and organizing training and other facilities

• Scheduling the training program

• Monitoring the progress of trainees.

• –How to make training effective :-

• allocate major resources and adequate time for training.

• Ensure that the training contributes to the strategies of the firms.

• Ensure a systematic and comprehensive approach.

• Make learning one of the fundamentals values of the company.

• Create a system to evaluate the effectiveness of the training.

• Ensure that there is proper linkage among organizational, operational and individual needs.

Training need and GMP requirement:-

–Every new employee shall be given Induction Training with a view to facilitate entry into the organization and to acquaint with the systems and procedures as applicable.

• SOP/On-the-job training shall be given to the employees in their respective areas of operation according to the training need identification of individual departments.

• During on-the-job training period, employees shall be trained for usage of equipment, unit operations, safety norms to be followed, Quality Assurance Procedures and Standard Operating Procedures, Validation and Calibration procedures, Preventive Maintenance as applicable.

 

– Training Log shall be maintained for each training.

• Evaluation shall be done by preparing a questionnaire based on the topics covered during the training.

Training shall be given in  Following Events:

• Introduction of new standard operating procedure.

• Change in SOP content, observation of audit, laboratory testing error, manufacturing error, document error etc.

Re-training of employees :

If an employee has been absent from the company or is returning to a specific task after a period of greater than six months, the need for re-training must be evaluated in association with the employee.

Training for contract Employee:-

• Training shall be conducted for workmen, housekeeping personnel and contract workmen of Specific working areas.

• Wherever required SOP shall be converted to vernacular language or training shall be imparted in vernacular language for better understanding of procedures to contract workers.

• Contract workers shall work under supervision of trained staff.

Trainer Certification:

• Trainer shall be assessed for skills like subject matter expert, subject understanding, presentation skill, training skills, communication skills, interaction skill, voice clarity etc.

THANK YOU