Thursday, January 6, 2011

Cleaning Validation Procedures

·        General concept
Ø      Three consecutive validations will be performed to prove that the method is validated.
Ø      Whenever a new product is introduced, equipment usage and nature of potential contaminant will be studied to assess whether it poses a challenging study for cleaning validation.
Ø      If the new product represents worst case, study/ identify/develop method of cleaning to be employed. Simultaneously develop Analytical method for cleaning and validate the same.
Ø      Revalidation Policy.
·        Level of cleaning:
Ø      Levels of cleaning during processing depends on:
o       Equipment usage (e.g. dedicated or not)
o       Stages of manufacturing
o       Nature of contaminant (e.g. solubility, toxicity, color etc.)
Ø      Our policy is to carry out cleaning after the end of each process, so that the equipment is clean and ready for the next use.
·        Elements of cleaning validation:
·        Cleaning validation study includes:
Ø      Cleaning Procedure
o       Identification of equipment
o       Characterization of products
o       Determination of cleaning agents
Ø      Analytical method and its validation
Ø      Sampling procedure
Ø      Establishment of acceptance criteria
Ø      Validation protocol
Ø      Validation Reports
·        Cleaning Procedure:
Ø      Prior to developing cleaning validation study, evaluate the following:
o       Identification of Equipments:
ü Identify equipments to be cleaned.
ü Identify difficult to clean areas
ü Check for ease of dismantling
o       Characterization of products:
ü  Study activity/toxicity, solubility of the active substance of current batch and dosage and batch size of next product to be taken on the equipment.
o       Determination of Cleaning Agents:
ü Identify cleaning agents to be used
ü Identify number of cleaning cycles
ü Identify equipments / materials to be used for cleaning.
o       Based on above, prepare detailed written cleaning procedures for each equipment.
·        Analytical Methods and its validation:
Ø      In order for the analytical testing of the cleaning validation samples to yield meaningful results, the analytical methods used should be validated.
Ø      Analytical method validation for cleaning should include limit of detection, limit of quantification, acceptance criteria and rationale for setting the specified limits.
·        Sampling Procedure:
Ø      Sampling plan for validation study should be drawn which includes:
Ø      Sampling technique: Type of Sampling methods to be used are,
o       Direct surface sampling by swab.
o       Rinse water sampling (for equipment cleaning).
o       Plate exposure (for area cleaning).
Ø      Sampling Locations:
o       Two easy to clean and two hard to clean areas should be clearly defined in Protocol.
Ø      Sampling Procedure:
o       Should mention how many samples are to be taken
ü Swab samples should be taken separately for chemical and microbiological studies
ü For each of chemical and microbiological analysis take 2 swabs from easy to clean hard to clean locations
ü How the samples are to be taken
Ø      Sample Numbering:
o       Swab samples should be numbered numerically and sequentially like 01, 02 etc for identification.
Ø      Establishment of Acceptance Criteria:
o       Based on the data available calculate acceptance criteria for both Pharmacological dose method and limiting the level of product to 10 ppm which appear in the following product.
o       Of these two, choose the criterion with stringent limits and detectable by analytical method.                                                                                          
o       Microbiological limit is 50 CFU/100 cm2. Per swab
·        Validation Protocol
Ø      Validation protocol defines protocol number.
Ø      Protocol defines a validation team that will be responsible for carrying out validation studies. Validation team comprises of at least one responsible person from production, QC & QA department.
Ø      Responsibilities of team member are:-
o       Production – Carrying out cleaning methods & implementing validation protocol.
o       Quality Control – Developing analytical method for cleaning, sampling, testing & recording the results.
o       Quality Assurance – Issuing & reviewing of protocol, supervision of validation activities.
Ø      Validation protocol given details location, product manufactured, profile of active ingredient, cleaning agents used, testing equipment to be used, sampling points, sampling procedures, limit of detection acceptance calculation, surface area, validation report etc.
Ø      Responsible persons from Production, QC and QA should formally approve the cleaning validation protocol.
Ø      After approval Validation protocol is issued to QC Department.
Ø      QC will perform validation studies in accordance with protocol and record results in validation report.
·        Validation Procedure:
Ø      After completion of the manufacturing process, workman will clean the equipment.
Ø      If the cleaned equipment is listed in the protocol, production person will inform QC Department to collect samples for testing and QA department for supervision.
Ø      QA/QC chemist will first check visually for cleanliness of equipment.
Ø      If it observed not clean, instruct for re-cleaning.
Ø      If it observed visually cleaned, collect samples separately for both chemical and microbial analysis (if required) from locations given in the protocol as per sampling procedure.
Ø      Samples are carried to QC, where testing of the samples will be done using validated Analytical method.
·        Validation Report:
Ø      QC will record the results of testing in the protocol.
Ø      QC will return the protocol with documented results and attachments like work sheet, graphs, chromatograms etc. to QA for review.
Ø      After completion of documented studies, QA will write conclusions regarding acceptability of the results and status of procedures considered for validation.
Ø      Any recommendations based on the documented results will be mentioned.
Ø      References to the procedures used for cleaning, sampling and testing should be mentioned in the validation report.
Ø      All the members of validation team should approve conclusion
Ø      In cases where it is unlikely that further batches of the product will be manufactured for a period of time, it is advisable to generate interim reports on batch-to-batch basis till such time the cleaning validation study is complete.
Ø      If the results of validation of any of the three studies are non-conforming to set limits of acceptance criteria, QC should inform immediately to QA.
Ø      Further manufacturing process on the equipment/in the area should be suspended.
Ø      Re-validation should be performed.
Ø      Prior to re-validation, cleaning methods/procedures, sampling methods/ procedures and analytical procedures employed should be re-checked and reviewed.
·        Re-validation Policy:
Ø      Revalidation of validated cleaning procedures will be considered –
o     Once in a year, three replicate studies will be performed.
o     In case of changes in equipment/process of product
Ø      If the new product represents worst-case challenge
1.0  The result of inadequate cleaning procedures is that any of a number of contaminants may be present in the next batch manufactured on the equipment such as:
o       Precursors to the Active Pharmaceutical Ingredient
o       By-products and/or degradation products of the Active Pharmaceutical
o       The previous product
o       Solvents and other materials employed during the manufacturing process.
o       Micro-organisms
         This is particularly the case where microbial growth may be sustained   by the product.
o       Cleaning agents themselves and lubricants
2.0 Cleaning techniques to be evaluated
o       Manual cleaning
o       CIP (Clean-in place)
o       COP (clean-out-of-place)
o       Semi automatic
o       Automatic
o       Time considerations
o       Number of cleaning cycles.

type Of Validation Procedures


Ø         prospective validation
Ø         concurrent validation
Ø         retrorospective validation
2)         cleaning validation
3)         change control
4)         Re- validation

Cleaning validation
Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, and toxicology and equipment size.
Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results.
Process validation
Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics
Concurrent validation
Validation carried out during routine production of products intended for sale.
Prospective validation
Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations.
Retrospective validation
Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged.
- The sources of data for this validation may include batch   documents, process control chart, maintaince logbook, records of personnel change process capability studies, fp data and stability results.
Validation report (VR)
A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment.

Process Validation Program
The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process
For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.
Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.
Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

Approaches to validation
5.1.1 There are two basic approaches to validation—one based on evidence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products.
5.1.2 Both prospective and concurrent validation, may include:
• extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity;
• simulation process trials;
• challenge/worst case tests, which determine the robustness of the process; and
• control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.
5.2 Scope of validation
5.2.1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved.
5.2.2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed.
5.2.3 There should be proper preparation and planning before validation is performed. There should be a specific programmed for validation activities.
5.2.4 Validation should be performed in a structured way according to the documented procedures and protocols.
5.2.5 Validation should be performed:
— for new premises, equipment, utilities and systems, and processes and procedures;
— at periodic intervals; and
— when major changes have been made. (Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required.)
5.2.6 Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced.
5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered.
5.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously.
5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality.
5.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A risk assessment approach should be used to determine the scope and extent of validation required.

Analytical Method Validation

There are many reasons for the need to validate analytical procedures. Among them
are regulatory requirements, good science, and quality control requirements. The
Code of Federal Regulations (CFR) 311.165c explicitly states that “ the accuracy,
sensitivity, specifi city, and reproducibility of test methods employed by the fi rm shall
be established and documented. ” Of course, as scientists, we would want to apply
good science to demonstrate that the analytical method used had demonstrated
accuracy, sensitivity, specifi city, and reproducibility. Finally management of the
quality control unit would defi nitely want to ensure that the analytical methods that
the department uses to release its products are properly validated for its intended
use so the product will be safe for human use.

The analytical method validation activity is not a one - time study. This is illustrated
and summarized in the life cycle of an analytical procedure in Figure 1 . An analytical

method will be developed and validated for use to analyze samples during the early
development of an active pharmaceutical ingredient (API) or drug product. As drug
development progresses from phase 1 to commercialization, the analytical method
will follow a similar progression. The fi nal method will be validated for its intended
use for the market image drug product and transferred to the quality control laboratory
for the launch of the drug product. However, if there are any changes in the
manufacturing process that have the potential to change the analytical profi le of the
drug substance and drug product, this validated method may need to be revalidated
to ensure that it is still suitable to analyze the API or drug product for its intended

General Concepts
Ø      Validation is the act of demonstrating and documenting a procedure that operates effectively.
Ø      The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedure:
R           Identification tests
R           Quantitative tests for impurities content
R           Limit tests for the control of impurities
R           Quantitative tests of the active moiety in samples of drug substance or drug product or other selected components in the drug product.
Ø      Typical validation characteristics which should be considered are:
R           Accuracy
R           Precision
R           Specificity
R           Quantitation Limit
R           Linearity and Range
R           Robustness
·        Method Validation Parameter for the assay of Mebendazole:
Ø      Linearity: Mebendazole to be analyzed as per proposed method. The results obtain is used to statistically evaluate for coefficient of determination (r2), standard error of estimate and y intercept.
Ø      Precision: Precision of the chemical method is ascertained by carrying out the analysis as per the procedure and as per normal weight taken for analysis. Repeat the analysis five times. Calculate the % assay, mean assay, % Deviation and % relative standard deviation and %RSD.
Ø      Accuracy: Accuracy of the method is ascertained by standard addition method at 3 levels. Standard quantity equivalent to 80%, 100% and 120% is to be added in sample.
·        Method Validation Parameter for residual solvent by GC for Mebendazole:
Ø      Specificity: Resolution of the analyte peak from the nearest peak: Solution of each of the analyte was injected separately and their retention time is noted. The standard working solution containing a mixture of the component being analyze is also injected and each of analyte peaks is check for its resolution from the nearest.
Ø      Precision:
R     Repeatability: Six replicate injections of standard solution for system precision should analyze as per the proposed method and from the chromatograms obtained the percentage % RSD is calculated.
R     Intermediate precision: The purpose of this test is to demonstrate the intermediate precision of the method when method is executed by a different analyst and on different day. Results obtained will be compared.
Ø      Linearity and Range: Solution of analyte solvent, having different concentration should make separate from L.O.Q. concentration, which is 50% to 150%. The result obtained is statistically evaluated for coefficient of determination (r2), standard error of estimate and y intercept.
Ø      LOD & LOQ:
R     The limit of Detection (L.O.D.) was calculated as per below equation:
                      LOD          =              3.3     X       SD

R     The limit of Quantification (L.O.Q.) was calculated as per below equation:
                                                LOQ         =              10      X     SD
Ø      Accuracy / % Recovery (By Standard Addition Method): Accuracy of the method was ascertained by standard addition method at 3 levels.
R     Standard solution quantity equivalent to 50%, 100% and 150% are added in sample.
R     The solutions amount is analyzed by the proposed method and chromatogram obtained.
R     The amount recover by the method is compared to the amount added. Percent deviation is calculated at each levels and a grand average across all the levels are also calculated.
Methanol standard concentration ––  3000 ppm
Acetic acid standard concentration –– 5000 ppm
DMF standard concentration ––          880  ppm
Ø      Robustness:
R     The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study. It should show the reliability of an analysis with respect to deliberate variations in method parameters.
R     If measurements are susceptible to variation in analytical conditions, the analytical condition should be suitably controlled or a precautionary statement should be included in the procedure.
R     One consequence of the robustness should be that a series of system suitability parameters (e.g. resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used.

The typical process that is followed in an analytical method validation is chronologically listed below:
1. Planning and deciding on the method validation experiments
2. Writing and approval of method validation protocol
3. Execution of the method validation protocol
4. Analysis of the method validation data
5. Reporting the analytical method validation
6. Finalizing the analytical method procedure
The method validation experiments should be well planned and laid out to ensure
effi cient use of time and resources during execution of the method validation. The best way to ensure a well - planned validation study is to write a method validation protocol that will be reviewed and signed by the appropriate person (e.g., laboratory management and quality assurance).
The validation parameters that will be evaluated will depend on the type of
method to be validated. Analytical methods that are commonly validated can be
classifi ed into three main categories: identifi cation, testing for impurities, and assay. Table 3 lists the ICH recommendations for each of these methods.
Execution of the method validation protocol should be carefully planned
to optimize the resources and time required to complete the full validation
study. For example, in the validation of an assay method, linearity and accuracy may be validated at the same time as both experiments can use the same standard solutions.
A normal validation protocol should contain the following contents at a
(a) Objective of the protocol
(b) Validation parameters that will be evaluated
(c) Acceptance criteria for all the validation parameters evaluated
(d) Details of the experiments to be performed
(e) Draft analytical procedure
The data from the method validation data should be analyzed as the data are
obtained and processed to ensure a smooth fl ow of information. If an experimental error is detected, it should be resolved as soon as possible to reduce any impact it may have on later experiments. Analysis of the data includes visual examination of the numerical values of the data and chromatograms followed by statistical treatment of the data if required.
Upon completion of all the experiments, all the data will be compiled into a
detailed validation report that will conclude the success or failure of the validation
exercise. Depending on the company ’ s strategy a summary of the validation data may also be generated. Successful execution of the validation will lead to a final analytical procedure that can be used by the laboratory to support future analytical work for the drug substance or drug product.

There are various circumstances under which a method needs to be revalidated.
Some of the common situations are described below:
1. During the optimization of the drug substance synthetic process, signifi cant
changes were introduced into the process. To ensure that the analytical method
will still be able to analyze the potentially different profi le of the API, revalidation
may be necessary.
2. If a new impurity is found that makes the method defi cient in its specifi city,
this method will need to be modifi ed or redeveloped and revalidated to ensure
that it will be able to perform its intended function.
3. A change in the excipient composition may change the product impurity
profi le. This change may make the method defi cient in its specifi city for the
assay or impurity tests and may require redevelopment and revalidation.
4. Changes in equipment or suppliers of critical supplies of the API or fi nal drug
product will have the potential to change their degradation profi le and may
require the method to be redeveloped and revalidated.