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 cm^2. 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

         Ingredient

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

T

1)         PROCESS VALIDATION

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.

Validation

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

WHY VALIDATE ANALYTICAL PROCEDURES ?

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.

CYCLE OF ANALYTICAL METHODS
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
purpose.

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

                                                                  Slope 

R     The limit of Quantification (L.O.Q.) was calculated as per below equation:

                                   

                                                LOQ         =              10      X     SD

                                                                                         Slope

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.

PROCESS OF ANALYTICAL METHOD VALIDATION
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
minimum:
(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.

METHOD REVALIDATION

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.

Why Validation is Important

Validation is a concept that has been evolving continuously since its first formal appearance in United States in 1978. The concept of validation has expanded through the years to encompass a wide range of activities which should take place at the conclusion of product development and at the beginning of commercial production. Validation is confirmation by examination and provision of objective evidence that the particular requirements for a specified intended use are fulfilled.

We all love validation!

Objective Measures

Validation is the overall expression for a sequence of activities in order to demonstrate and document that a specific product can be reliably manufactured by the designed process, usually, depending on the complexity of today’s pharmaceutical products, the manufacturer must ensure. Quality cannot be adequately assured merely by in-process and finished product inspection or testing so the firms should employ objective measures (e.g. validation) wherever feasible and meaningful to achieve adequate assurance.
Today we have different definitions of validation, which are as follows-

• Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.
• The collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.
• Validation is a process by which a procedure is evaluated to determine its efficacy and reliability for forensic casework analysis.

Why Validation is Important

The principles – Quality, Safety and Effectiveness must be designed and built in to the product, quality cannot be inspected or tested in the finished products and each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications. Now let me explain the specific importance of the validation – it is the concept detailed in quality guidelines of Product Lifecycle and with the help of which we can do the following:

• Determine the process parameters and necessary controls.
• To confirm the process design as capable of reproducible commercial manufacturing.
• Risk/Worst Case assessment. What is Worst Case? It is a set of conditions encompassing upper and lower limits and circumstances, including those within standard operating procedures, which pose the greatest change of process or product failure when compared to the ideal conditions.
• To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives.
• Quantitatively determine the variability of a process and its control.
• The variability within and between batches can be evaluated to determine the inner and intra-batch variability.
• Greater scrutiny of the process performance for development and deployment of process controls.
• Scientific study performed prior to implementing a change to a process can support the implementation of a change without revalidation.
• Safeguard and process against sources of variation which may not have been identified during the original process development.
• The most compelling reason to optimize and validate pharmaceutical productions and supporting processes and cost reduction.
• Control point in the context of preventive maintenance.
• Investigate deviations if any from established parameters.

Conclusion

Validation allows us to focus on our everyday business operations of making and selling quality products that also comply with regulatory requirements such as the FDA, Schedule M, etc. The industry which has adopted a lifecycle approach to the product development, validation and modern risk analysis tools can control critical process parameters. The companies can create a new standard of industry best practice by embracing the ability of validation practices which will lead in technological revolution.

Critical Parameters Affecting Process Validation

Validation is an integral part of quality assurance; it involves systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control. Adequate validation is beneficial to the manufacturer in many ways – It deepens the understanding of processes; decreases the risk of preventing problems, defect costs, regulatory non compliances and thus assures the smooth running of the process.

Process Validation is key to a robust manufacturing process

Process validation involves a series of activities taking place over the lifecycle of product and process. Validation requires a meticulous preparation and careful planning of the various steps in the process. All work involved should be carried out in a structured way according to formally authorized standardized working procedures.

What are the Critical Parameters affecting Process Validation?

The critical parameters should normally be identified during the development stage or from historical data or during manufacturing and process control. Process validation involves three stages and now will identify the critical parameters in these stages.

Stage One: Process Design

Process design is the activity of defining the commercial manufacturing process. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes. A product development activity provides key inputs to the design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. The functionality and limitations of commercial manufacturing equipment should be considered, also contributions of variability by different component lots, production operators, environmental conditions and measurement systems in the production setting.
Designing an efficient process with an effective process control approach is dependent on the process knowledge. Use of risk analysis tools to screen potential variables for Design of Experiment (DOE) studies to minimize the total number of experiments. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters and in-process material quality attributes. Manufactures should document the variables studied for a unit operation and the rationale for those variables identified as significant. This information is useful during the process qualification and continued process verification stages, including the design is revised or strategy for control is refined.
Process control addresses the variability to assure quality of the product. Controls can consists of material analysis and equipment monitoring at significant processing points designed to assure that the operation remains on target and in control with respect to output quality. Timely analysis, control and adjust the processing conditions so that the output remains constant.

Stage Two: Process Qualification

During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. It confirms that all established limits of the critical parameters are valid and that satisfactory products can be produced even under worst case condition. This stage has following elements –Qualification of Utilities and Equipment.
Installation Qualification is an essential step preceding the Process Validation exercise which is normally executed by Engineering group. The installation of equipment should follow well defined plans which is developed and finalized following progression through a number of design stages. This stage of validation includes examination of Equipment Design, Determination of Calibration, Maintenance and Adjustment Requirements.
Consider the following Equipment Calibration Requirements
1. Confirmation of calibration of calibrating equipment with reference to the appropriate national standard.
2. Calibration of measuring devices utilized in the Operational Qualification stage.
3. Identification of calibration requirements for measuring devices for the future use of the equipment. At the Installation Qualification stage the company should document preventive maintenance requirements for installed equipment.
Operational Qualification is an exercise oriented to engineering function referred as commissioning. It is important stage to assure all operational test data conform with pre-determined acceptance criteria and manufacturer should develop draft standard operating procedures for the equipment, service operation, cleaning activities, maintenance requirements and calibration schedules.
The critical operating parameters for the equipment or the plant should be identified at the Operational Qualification stage. Critical variables should incorporate specific details and tests that have been developed. The completion of a successful Operational Qualification should include the finalization of operating procedures and operator instructions documentation for the equipment.
Performance Qualification combines the actual facility, utilities, equipment, trained personnel, control procedures and components to produce commercial batches. Performance qualification will have a higher level of sampling, additional testing and greater scrutiny of process performance. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during process.

Stage Three: Continued Process Verification

Continually assure that the process remains in a state of control during commercial manufacturing. A system or systems for detecting unplanned departures from the process as designed is essential. The following points to be considered in Continued Process Verification.
Collection and evaluation of information and data about the performance of the process will allow detection of process drift. Evaluation should determine whether action must be taken to prevent the process from drifting out of control.
An ongoing program to collect and analyze product and process data that relate to product quality must be established to verify the critical quality attributes are being controlled throughout the process.
Process variation also can be detected by assessment of defect complaints, out of specifications finding, process deviation reports, process yield variations, batch records, incoming raw material records and adverse event reports.
Operator’s errors should be tracked to measure the quality of the training program.
Maintenance of the facility, utilities and equipment is an important aspect of ensuring that a process remains in control.

Conclusion

Process validation is a mean of ensuring and documenting that the processes are capable of producing a finished product of the required quality consistently and should cover all the critical elements of the manufacturing process. The process design stage and the process qualification stage should have as a focus the measurement system and control loop establishing scientific evidence that the process is reproducible and will consistently deliver quality products.
Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, appropriate alert and action limits. Process variability should be periodically assessed. It is the responsibility of the manufacturer to judge and provide evidence of a high degree of assurance in its manufacturing process.

References

• Guidance for Industry Process Validation: General Principles and Practices – US Dept. of Health and Human Services, Food and Drug Administration. Nov. 2008 Current Good Manufacturing Practices.
• ANNEX 15. Validation Master Plan, Design Qualification, Installation and Operational Qualification, Non Sterile Process Validation, Cleaning Validation. 17th Sep. 1999.

Good Documentation Practices (GDP) are Critical to Success!

Good Documentation Practices (GDP) are critical to the success of any operation or project within a regulated industry. Deployed [usually] via a Document Management Plan in accordance with Standard Operating Procedures (SOPs), GDP is cascaded through an organisation to enable consist, correct entries being made on and to documentation.

GDP requires a consistent approach

There is a more than one way to skin a cat, one might say so there is certainly more than one way to work with documents and for this reason alone GDP is critical. For example, you have a group of operators making up a batch of drugs on a rotating shift basis – they’re all completing the relevant batch records whilst adhering to the SOPs governing the make-up; the drugs are made [probably correctly], however upon QA review the specialist doesn’t fully understand some of the entries in the batch record.
There are blank spaces in some, date formats are different (EU vs US); felt pens, highlighters and biros are used to make the entries and mistakes are left scribbled out, ripped off or just left. How can the company stand over the integrity of the drugs when their own internal QA specialists can’t understand the batch records?
Answer: They can’t.
What next? Drugs in the bin, poor documentation equals poor assurance and that means lost revenue at best and lost customers or patient risk at worst!

How can we improve?

Remedy: Good Documentation Practices. If everyone is utilising the same set of documentation rules, whether this be the people making drugs or the people checking HVAC (Heating, Ventilation and Air Conditioning) logbooks the message is clear. Follow the procedures or your work won’t be acceptable. If everyone handles mistakes with a single-strikethrough and initials and dates modifications, paginates in the form x of y; everything is consistent. Everyone can understand and QA reviews can be successful leading to getting product out the door.

Have clear training requirements

Good Manufacturing Practices (GMP) are fundamental to the success of drug manufacturing; GDP is fundamental to GMP. But how is this achieved? Training. Plain and simple. Training all personnel as to the criticality of GDP is essential. Show them how it is done, show them how is shouldn’t be done – make sure each person has a curricula detailing their training requirements and make sure training is fully documented and in cases of great importance such as GDP make sure there is an assessment so that the trainee can be verified to have understood the course.
Training doesn’t have to take long, it just has to be right. 30 to 60 minutes is sufficient to train people in the use of GDP – but make sure a robust document management plan is in existance first, use this as the driver to push out the importance of GDP, ensure that all documentation eventualities are addressed from labelling and cross referencing attachments to the usage of tip-ex (or rather not to ever use tip-ex – this is simply forbidden).
Work instructions are SOPs and will implement the requirements of the document management plans so that GDP simply can’t go un-noticed, after all if people are trained in procedures that they aren’t following properly this is going against the grain of the job brief as well as moving the business out of compliance in certain areas, which of course is completely unnacceptable, leaving the offenders open to disciplinary action.

GDP is here to stay

Clearly and simply, or rather to be blunt – GDP is here to stay and once proper procedures have been established, users trained and the wheels are in motion there is no turning back. QA will reject illegal entries and users will simply just apply GDP, well it is better than the sack. Once these have been implemented it will be quite difficult to NOT understand the point whilst at the same time people won’t be able to wonder why or how they were even there before GDP.

When is GDP applicable?

When is GDP applicable? Officially, when completing documentation that supports the manufacture of drug products or offical materials, the storage, holding and distribution of goods are within the remit of GDP to name but a few. Professionally, it is good practice to apply GDP always – even when handling documents relating to test and development systems. If nothing else, GDP is as much part of Good Engineering Practice (GEP) as it is relevant to GMP, if in doubt apply GDP. At least you’ll sleep safely at night without worrying about noise in the night been your boss at the door.

GDP all the way!

Enforcement. The Document Management Plan should detail how these documents should be verified to be correct. We’ve already mentioned QA reviewing batch records but they don’t necessarily get to see everything and to this end documents that are deemed to fall under the GDP umbrella should be audited to verify that people completing GDP entries are doing so correctly; this is standard practice and is a useful exercise, after all it is better identifying and resolving such issues sooner than later; the consequences of the FDA or EMEA findings faults during their own audits doesn’t bear thinking about!
So, GDP or not GDP? I think I’m safely on the GDP side of the fence, how about you? Plan to succeed with GDP and ensure your systems are set up properly. Otherwise you’ve simply failed by virtue of failing to plan!! Don’t delay, write your document management plan today!