pharmaceutical validation

Cleaning Validation Procedures

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· 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

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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

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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

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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

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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!

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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!

Cleaning Validation Methods

2010-12-14T00:44:00.000-08:00

leaning can be defined as the removal of residues from previous batch, other residues, and traces of cleaning agents. There are several mechanisms associated with cleaning of equipment. The mechanisms involved can be mechanical action, chemical action between the residues and the cleaning agent. The selection of cleaning agent and mechanism involved in cleaning is largely dependant on the process residue to be cleaned.

Cleaning Validation Mechanisms

Cleaning Mechanisms

The cleaning mechanism totally depends on the selection of cleaning agent and type of residue to be cleaned. Following can be the one of the methods involved in cleaning of residues,

Dissolution
Saphonification
Wetting
Emulsifying

Many cleaning compound agents perform several functions at once. Butyl, for instance, can serve as a wetting or surface tension reducing agent as well as a solubilizing agent. It also can contribute to emulsifying capabilities when combined with anionic surfactants or soaps (alkali-metal salts of carboxylic acids).

Dissolution

Dissolution is the process by which a solid or liquid forms a homogeneous mixture with a solvent or solution. This can be explained as a breakdown of the crystals into individual ions, atoms or molecules and their transport into the solvent
The mechanism involved in this type of cleaning is solubility of the residue in the cleaning agent or solvent. The monobasic buffers i.e. sodium chloride are soluble in cool and hot WFI. Ethylene glycol butyl ether is soluble in water as well as oil is also used in solubilizing agent. Chelating agents and builders are added to the formula to keep water hardness from interfering with the cleaning process.
Rate of dissolution is depend on,

Nature of solvent or residue to be dissolved
Temperature of solvent
Presence of mixing
Area of contact
Presence of inhibitors

Saphonification

Saponification can be defined as “hydration reaction where free hydroxide breaks the ester bonds between the fatty acids and glycerol of a tri-glyceride, resulting in free fatty acids and glycerol”, which are each soluble in aqueous solutions.
This process specifically involves the chemical degradation of lipids, which are not freely soluble in aqueous solutions. Heat treated lipid residues are difficult to remove than non-heat residues due to polymerization.
Saphonification plays a critical role in cleaning lipids which are present in the areas of process involving cell growth and cell processing i.e. Bacterial fermentation, Cell disruption process

Wetting

Wetting can be defined as a process “involves the lowering of the surface tension of the cleaning solution, thus allowing it to better penetrate residues that are adhered to equipment and piping surfaces”. Wetting agents, or surfactants, are often used in relatively small amounts and they can substantially reduce the quantities of cleaning agent (in this case, alkali) required for residue removal.
Advantages of Wetting

Lowers the surface tension of the cleaning solution
Allow better penetrate residues which are adhered to equipment
Used in small amount
Sticky residues which are hydrophobic in nature get easily removed

Water acts as a solvent that breaks up soil particles after the surfactants reduce the surface tension and allow the water to penetrate soil (water is commonly referred to as “the universal solvent”).

Emulsifying

Emulsifying and suspending agents are often used to keep residues from precipitating by providing “hydrophobic groups” onto which hydrophobic areas of residues can associate, thus preventing them from associating with other residues and forming larger particles which are likely to leave solution. These agents also typically have “hydrophilic groups” which keep them very soluble in aqueous solutions of moderate to high ionic concentrations. Emulsifiers increase the capacity of a cleaner to emulsify non-soluble compounds in the cleaner. i.e. anionic soap surfactants, cationic surfactants, neutral surfactants
Advantages of Emulsifying agents,

Prevent association of residues
Allow the residue to precipitate and not allow thdse residue to redeposit on surface

Cleaning In Place (CIP) Vs Cleaning Out of Place (COP)

2010-12-14T00:39:00.001-08:00

The basic regulatory requirement is to provide pharmaceutical products of highest quality to the patients. A cleaning problem can have various consequences to health, economics, environment and regulatory approvals. Absence of good cleaning, leads to contaminated drugs, which pose risks for patients as well as manufacturing personnel. Regulatory risk includes possible removal of authorization. Economical risk involves production delays and stock shortages or losses but also manifest as public relations problems for a company.
There are four main cleaning processes used in regulated environments. These include:

Cleaning-in Place (CIP)
Cleaning-out-of-place (COP)
Manual Cleaning
Immersion Cleaning

So whats the difference between all of these cleaning techniques?

Cleaning In Place (CIP)

Cleaning in place can be described as the cleaning of equipment and vessels at the same place without movement of them to a different place. The cleaning agents can be transferred to the vessel or equipment types either thorough fixed piping or flexible hoses.
The CIP process can consist of the following elements:

Supply pump
Return pump
Heat exchanger with Black/Plant steam supply
Chemical tanks i.e Acid, Alkali tanks
Supply Pressure gauge or transmitter
Supply temperature sensors
Conductivity meter with sensor

Cleaning Out of Place (COP)

Cleaning Out of Place is defined as a method of cleaning equipment items by removing them from their operational area and taking them to a designated cleaning station for cleaning. It requires dismantling an apparatus, washing it in a central washing area using an automated system, and checking it at reassembly.

Manual Cleaning

Manual cleaning is the universal practise among the pharma and biopharma industries. The design, configuration and construction of equipment or the whole equipment which necessities the manual cleaning for the piece of equipment. The efficiency of the manual cleaning accomplished by training the cleaning operators, ensuring exact method of cleaning in the manual cleaning SOP, validating the method from different operators and verifying the procedure with interval of time.
The manual cleaning is dependent on,

Concentration of detergent used
Temperature of washing liquid

Immersion Cleaning

This is the type of cleaning in which the parts to be cleaned are placed in the cleaning solutions to come in contact with the entire surface of the parts.
Immersion cleaning is preferred for parts that must be placed in baskets and for processes requiring a long soaking time because of the type of contamination to be removed or the shape of the parts to be cleaned.
It is the most effective method, even if not the fastest one, and can be used with any type of cleaner for any process, heated or at room temperature. Immersion washers can be portable or stationary; single or multi-compartment; and are available with a variety of options, controls and valve configurations including CIP capability.
The important aspects during design of immersion washer should be

To minimize cycle time
Lower chemical usage
Reduce water and utility costs

Performance for immersion cleaning can be improved by moving the parts within the liquid or with agitation of the liquid, mechanically or with the addition of ultrasonic energy.

Cleaning Validation Forum

If you would like to learn more about CIP or COP please read the following threads:

Criteria of determination of cleaning of residue
Post Cleaning Rinsing
Cleaning Validation Conclusion Report
Cleaning Validation Calculation

Process Robustness in Pharmaceutical Manufacturing

2010-12-14T00:37:00.000-08:00

The objective of this study is to unify understanding of the current concepts of process robustness and application of robustness principles to non-sterile solid dosage form manufacturing. Process robustness activities start at the earliest stages of process design and continue throughout the life of the product, it suggests greater process certainty in terms of yields, cycle times and level of discards.

Process Robustness in Pharmaceutical Manufacturing

An assessment of process robustness can be useful in risk assessment, reduction, potentially be used to support future manufacturing and process optimization. Robustness cannot be tested into a product; rather it must be incorporated into the design and development of the product. Performance of the product and process must be monitored throughout scale up, introduction and routine manufacturing to ensure robustness is maintained.

Principles Of Process Robustness

Definition of Robustness –

“The ability of a process to demonstrate acceptable quality and performance while tolerating variability.”

Process performance and variability may be managed through the choice of manufacturing technology. Well designed processes reduce the potential for human mistakes, thereby contributing to increased robustness. During product and process development both the inputs and outputs of the process are studied to determine the critical parameters and attributes for the process, the tolerances for those parameters and how best to control them. Critical Quality Attributes, Process Parameters, Process Capability, Manufacturing and Process Control Technologies and Quality System Infrastructure are referred as Manufacturing Science underlying a product and process. Principles of process robustness are as follows –
(A) Critical Quality Attributes (CQAs) – The identified measured attributes that are deemed critical to ensure the quality requirements – intended purity, efficacy and safety of an intermediate or final product, termed as Critical Quality Attributes.
(B) Critical Process Parameters (CPPs) – Is a process input that, when varied beyond a limited range has a direct and significant influence on a Critical Quality Attribute. It is important to distinguish between parameters that affect critical quality attributes and parameters that affect efficiency, yield, worker safety or other business objectives. Most processes are required to report an overall yield from bulk to semi-finished or finished product. It is important to have an understanding of the impact of raw materials, manufacturing equipment control, degree of automation or prescriptive procedure necessary to assure adequate control.
(C) Normal Operating Range (NOR) and Proven Acceptable Range (PAR) – In developing the manufacturing science a body of experimental data is obtained and the initially selected parameter tolerances are confirmed or adjusted to reflect the data. This becomes the Proven Acceptable Range for the parameter, and within the PAR an operating range is set based on the Normal Operating Range for the given parameter. In a robust process, critical process parameters have been identified and characterized so the process can be controlled within defined limits for those CPPs. A process that operates consistently in a narrow NOR demonstrates low process variability and good process control. The ability to operate in NOR is a function of the process equipment, defined process controls and process capability.
(D) Variability: Source and Control – Typical sources of variability includes process equipment capabilities, calibration limits, testing method variability, raw materials, human factors for non automated processes, sampling variability and environment factors within the plant facility.
(E) Setting Tolerance Limits – Upper and lower tolerances around a midpoint within the PAR of a parameter should be established to provide acceptable attributes. The defined limits should be practical and selected to accommodate the expected variability of parameters while confirming to the quality attribute acceptance criteria.

Development Of A Robust Process

A systematic team-based approach to development is one way to gain process understanding and to ensure that a robust process is developed. The following are the steps for the development of a robust process –
(1) Form the Team – Development of a robust process should involve a team of technical experts from R&D, technology transfer, manufacturing, statistical science and other appropriate disciplines. This team approach to jointly develop the dosage form eliminates the virtual walls between functions, improves collaboration and allows early alignment around technical decisions leading to a more robust product. This team should be formed before optimization and scale-up.
(2) Define the Process – A typical process consists of a series of unit operations. Before the team can proceed with development of a robust process they must agree on the unit operations they are studying and define the process parameters and attributes. Defining the process is to list all possible product attributes and agree on potential Critical Quality Attributes. The final step in defining the process is determining process parameters. Categorizations of parameters to consider are materials, methods, machines, people, measurement and environment.
(3) Prioritize Experiments – It is recommended that the team initially use a structured analysis method such as a prioritization matrix to identify and prioritize both process parameters and attributes for further study. A ranking of parameters of importance is calculated by considering the expected impact of a parameter on attributes as well as the relative importance of the attributes.
(4) Analyze Measurement Capability – The analysis of a process cannot be meaningful unless the measuring instrument used to collect data is both repeatable and reproducible. Analysis should be performed to assess the capability of the measurement system for both parameters and attributes. Measurement tools and techniques should be of the appropriate precision over the range of interest for each parameter and attribute.
(5) Identify Functional Relationship Between Parameters and Attributes – The functional relationships can be identified through many different ways, including computational approaches, simulations or experimental approaches. Design of Experiments is the recommended approach because of the ability to find and quantitate interaction effects of different parameters. Properly designed experiments can help maximize scientific insights while minimizing resources because of the following –

The time spent on planning experiments in advance can reduce the need for additional experiments.
Fewer studies are required and each study is more comprehensive.
Multiple factors are varied simultaneously.

(6) Confirm Critical Quality Attributes and Critical Process Parameters – After a sufficient amount of process understanding is gained, it is possible to confirm the Critical Quality Attributes previously identified. Critical Process Parameters are typically identified using the functional relationships from step 5 (Identify Functional Relationship Between Parameters and Attributes).

Conclusion

The pharmaceutical manufacturers should implement robust manufacturing processes that reliably produce pharmaceuticals of high quality and that accommodate process change to support continuous process improvement. Creating a system that facilitates increased process understanding and leads to process robustness benefits the manufacturer through quality improvements and cost reduction. The goal of a well characterized product development effort is to transfer a robust process which can demonstrate, with a high level of assurance, to consistently produce product meeting pre-determined quality criteria when operated within the defined boundaries.

References

PQRI Workgroup Members. Process Robustness – A PQRI White Paper. Pharmaceutical Engineering The Official Magazine of ISPE November/December 2006; Available from: http://www.06ND-online_Glodek-PQRI.pdf
Taguchi G., Y. Wu., A. Wu. Taguchi Methods for Robust Design. American Society of Mechanical Engineers 2000.
Johnson D. B., Bogle I. D. L. A Methodology for the Robust Evaluation of Pharmaceutical Processes under Uncertainty. Chem. Papers 54 (6a) 398-405 (2000).
Innovation and Continuous Improvement in Pharmaceutical Manufacturing (Pharmaceutical CGMPs for the 21st Century) The PAT Team and Manufacturing Science Working Group Report: A Summary of Learning, Contributions and Proposed Next Steps for moving towards the “desired State” of Pharmaceutical Manufacturing in the 21st Century. Available from: http://www.2004-4080b1_01_manufSciWP.pdf.

Validation Process in Pharmaceutical Industry

2010-12-14T00:35:00.000-08:00

Validation is a method to keep a check on the specific process, whether the ongoing process is able to meet the desired requirements. The definition of Validation as given by GMP is "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 attributes.”

Validation documentation includes analytical information, reports determining development, formulae which are used in the manufacturing process, standard operating procedures, development reports. Documentation also provides with the information for the currently running process. Activities performed under Validation will incorporate a level of Impact Assessment to ensure that systems, services and products directly influenced by the testing have been identified.

Validation process is conducted in various ways, some of them are:
Prospective validation
Under this kind of validation, a documented evidence is made defining, that a process will do, what it is supposed to do. And this specification is based upon a pre planned series of scientific tests as defined in the validation plan.

Concurrent validation
This kind of validation comes in a picture when an existing process is in a state of control because of various tests applied on samples throughout a process and when, same can be shown. For the documentation to be presented, all data is collected with the proper implementation of the process. Moreover, collecting of data continuous till sufficient information is available to demonstrate process reproducibility.

Retrospective validation
Finally Retrospective validation is documented, which is actually based on review and analysis of historical data. This particular validation defines, that a process does what it purports to do

Concept of Process Validation For Pharmaceutical Industry

2010-12-13T23:29:00.000-08:00

Concept of Validation
According to GMP definition Validation is "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 attributes."
Appropriate and complete documentation is recognized as being crucial to the validation effort. Standard Operating Procedures (SOPs), manufacturing formulae, detailed batch documentation, change control systems, investigational reporting systems, analytical documentation, development reports, validation protocols and reports are integral components of the validation philosophy. The validation documentation provides a source of information for the ongoing operation of the facility and is a resource that is used in subsequent process development or modification activities.
All validation activities will incorporate a level of Impact Assessment to ensure that systems, services and products directly influenced by the testing have been identified.
A revalidation program should be implemented based on routine equipment revalidation requirements and on the Change Control Policy.
Types of Validation
Prospective validation
Establishing documented evidence that a piece of equipment/process or system will do what it purports to do, based upon a pre-planned series of scientific tests as defined in the Validation Plan.
Concurrent validation
Is employed when an existing process can be shown to be in a state of control by applying tests on samples at strategic points throughout a process; and at the end of the process. All data is collected concurrently with the implementation of the process until sufficient information is available to demonstrate process reproducibility.
Retrospective validation
Establishing documented evidence that a process does what it purports to do, based on review and analysis of historical data.
Design Qualification (DQ)
The intent of the DQ is met during the design and commissioning process by a number of mechanisms, which include:
- Generation of User Requirement Specifications
- Verification that design meets relevant user requirement specifications.
- Supplier Assessment /Audits
- Challenge of the design by GMP review audits
- Product Quality Impact Assessment
- Specifying Validation documentation requirements from equipment suppliers
- Agreement with suppliers on the performance objectives
- Factory Acceptance Testing (FAT), Site Acceptance Testing (SAT) & commissioning procedures
- Defining construction and installation documentation to assist with Installation Qualification (IQ).
Installation Qualification (IQ)
IQ provides documented evidence that the equipment or system has been developed, supplied and installed in accordance with design drawings, the supplier's recommendations and In-house requirements. Furthermore, IQ ensures that a record of the principal features of the equipment or system, as installed, is available and that it is supported by sufficient adequate documentation to enable satisfactory operation, maintenance and change control to be implemented.
Operational Qualification (OQ)
OQ provides documented evidence that the equipment operates as intended throughout the specified design, operational or approved acceptance range of the equipment, as applicable. In cases where process steps are tested, a suitable placebo batch will be used to demonstrate equipment functionality.
All new equipment should be fully commissioned prior to commencing OQ to ensure that as a minimum the equipment is safe to operate, all mechanical assembly and pre-qualification checks have been completed, that the equipment is fully functional and that documentation is complete.
Performance Qualification (PQ)
The purpose of PQ is to provide documented evidence that the equipment can consistently achieve and maintain its performance specifications over a prolonged operating period at a defined operating point to produce a product of pre-determined quality. The performance specification will reference process parameters, in-process and product specifications. PQ requires three product batches to meet all acceptance criteria for in-process and product testing. For utility systems, PQ requires the utility medium to meet all specifications over a prolonged sampling period.
The PQ documentation should reference standard manufacturing procedures and batch records and describe the methodology of sampling and testing to be used.
What Gets Validated
General
All process steps, production equipment, systems and environment, directly used for the manufacture of sterile and non sterile products must be formally validated.
All major packaging equipment and processes should be validated. This validation is less comprehensive.
All ancillary systems that do not directly impact on product quality should be qualified by means of a technical documentation of the extent of the system and how it operates.
Facility
- Manufacturing Area Design.
- Personnel and material flow etc.
Process and Equipment Design
Process steps and equipment description. i.e. Dispensing, Formulating, Packaging, Equipment washing
and cleaning. etc
Utility Systems Design
Raw/purified steam, Purified water, Compressed Air, Air conditioning system, Vacuum, Power supply, Lighting, Cooling water, Waste etc
Computerized Systems Design
Information system, Laboratory automated equipments, Manufacturing automated equipments, Electronic records etc
Cleaning Validation (CV)
CV provides documented evidence that a cleaning procedure is effective in reducing to pre-defined maximum allowable limits, all chemical and microbiological contamination from an item of equipment or a manufacturing area following processing. The means of evaluating the effectiveness of cleaning involves sampling cleaned and sanitized surfaces and verifying the level of product residues, cleaning residues and bacterial contamination.
The term CV is to be used to describe the analytical investigation of a cleaning procedure or cycle. The validation protocols should reference background documentation relating to the rationale for "worst case" testing, where this is proposed. It should also explain the development of the acceptance criteria, including chemical and microbial specifications, limits of detection and the selection of sampling methods.
Method Validation (MV)
MV provides documented evidence that internally developed test methods are accurate, robust, effective, reproducible and repeatable. The validation protocols should reference background documentation relating to the rationale for the determination of limits of detection and method sensitivity.
Computer Validation
Computer Validation provides documented evidence to assure systems will consistently function according to their pre-determined specifications and quality attributes, throughout their lifecycle. Important aspects of this validation approach are the formal management of design (through a specification process); system-quality (through systematic review and testing); risk (through identification and assessment of novelty and critical functionality) and lifecycle (through sustained change control).
Where equipment is controlled by embedded computer systems, elements of computer validation may be performed as part of the equipment IQ and OQ protocols.

General process, cleaning and methodology validation concepts are described in this article with a special view to pharmaceutical industry

Definition of Validation Protocol

2010-11-30T02:52:00.001-08:00

Definition of Validation Protocol

By Katina Blue, eHow Contributor

updated: September 11, 2010

Validation protocol ensures that specific procedures are followed correctly.

Validation protocol is a means of testing a process to ensure its effectiveness or validity. It helps businesses and other organizations reach specific goals through tests and examinations.

Purpose

Validation protocol helps determine whether certain rules or procedures are being done correctly. It employs specific instructions or guidelines that must be followed to accomplish an end result.

Example

Businesses use validation protocol for various reasons, including evaluating the final construction of a product. For instance, an auto manufacturing plant could devise certain guidelines and tests to measure how well employees are assembling parts. The tests would evaluate how the part is constructed from beginning to end based on the given set of rules. The use of tests to measure the success of an outcome, such as a properly crafted auto part, is a form of validation protocol.

Benefits

Validation protocol is useful for businesses, universities, hospitals and any other entities that need to attain specific goals. It helps companies and individuals assess if products are created according to standards. It also aids in ensuring that the desired outcome of a procedure is achieved.

Definition of Process Validation

2010-11-30T02:51:00.001-08:00

Process validation is important to a wide range of industries, particularly that of pharmaceutical production. Without process validation, manufactured products would be both inconsistent and substandard.

Definition

Process validation is a procedure used to ensure that a certain process produces consistent, desirable results over a period of time. It guarantees that a given method for making products allows them to meet predetermined standards in a cost-effective way.

Areas Inspected

When a process undergoes validation, inspectors begin by checking to see that the equipment used in the process operates properly. Then, they check the results to make sure they fully meet quality standards. Finally, they observe the process over a period of time to ensure that the results are consistent.

Results

After observing these three areas, professionals compare the results to see if they match up with a predetermined set of standards. The process is then either validated or adjusted to make it fit the company's requirements.

Pharmaceuticals

Process validation is especially important to the pharmaceutical industry, because drug companies must be certain that their products are consistently identical. Because of this, the FDA strictly regulates process validation in this area.

Microbiological Aspects of Process Validation

2010-09-29T11:22:00.000-07:00

EtO Sterilization: Microbiological Aspects of Process Validation

Deliberate decision making during the structuring of microbial challenges, product loads, and biological indicators can provide a validation process for EtO sterilization that ensures accuracy, the absence of microbes, and a smooth testing procedure.

Susan Edel Satter and Paul J. Sordellini

A companion to this article, EtO Sterilization: Principles of Process Design, discussed the components of each phase of two 100% EtO with nitrogen processes, focusing on the engineering aspects of designing EtO cycles.¹ This article focuses on various approaches to medical device sterilization cycle validation from a microbiological standpoint. The discussion assumes that the first two stages of the validation—the commissioning and the physical performance qualification of the sterilization chamber—have been successfully completed. Therefore, this discussion deals solely with the third stage of EtO validation: the microbiological performance qualification (MPQ). The topics that are discussed include how to choose the appropriate microbial challenge for an EtO sterilization process, approach to developing the EtO cycle, product load, placement of biological indicators in/on the product load, method for determining cycle lethality, and calculations to determine the D-value.

Information is also given on the documentation for the report on validation and certification of the process, and revalidation is discussed briefly. Some suggestions exceed the current requirements presented in international standards, but they can enhance a validation process, resulting in a more thorough and accurate study.

International standards ISO 9001 and 9002 present the quality system requirements for the design, development, production, installation, and servicing of healthcare products. The ISO 9000 series treats medical device sterilization as a special manufacturing process because the results cannot be verified by inspecting and testing 100% of the product at the conclusion of the cycle. Sterilization processes must, therefore, be assessed for special considerations, validated prior to use (or during use in certain situations), and routinely monitored.

To design an effective validation and routine control program for a sterilization process, the bioburden on the product and packaging must be considered. Bioburden is defined as "the population of viable microorganisms on a product and/or a package" and is characterized in terms of number, identity, and resistance. A validated test method must demonstrate that it can consistently and adequately remove the bioburden from the product and packaging. There are various bioburden test methods and associated validation procedures from which to choose.²

Many factors can contribute to the bioburden on product and packaging, including the origin of the raw materials and components, transit and storage conditions, and the manufacturing environment in which the finished products are assembled and packaged. European standards place particular emphasis on controlling the processes used to manufacture sterile products.³

Sterility is defined as the "state of being free from viable microorganisms."⁴ Microbial death relating to the gaseous sterilization of healthcare products is an exponential function typically defined as the probability of a nonsterile item existing per a given number of units in a batch. This probability, called the sterility assurance level (SAL), defines the "probability of a viable microorganism being present on a product unit after sterilization."⁴ While sterilization can reduce the bioburden on a given product to a very low number, that probability can never be reduced to zero. Therefore, in order to achieve the desired bioburden levels, it is critical to design a validation program that provides a high degree of confidence for consistent sterilization.

DETERMINING THE APPROPRIATE MICROBIAL CHALLENGE

A biological indicator (BI) is an "inoculated carrier contained within its primary pack providing a known resistance to the relevant process."⁴ There are many different types of BIs but the most common include:

Commercial units supplied with the manufacturer's certification, such as bacterial spore strips individually packaged in glassine envelopes or pieces of filter paper impregnated with a certified population of a challenge organism that has a known resistance to EtO, such as the spores of Bacillus subtilis var. niger.
A liquid bacterial spore suspension commercially sold and certified by the manufacturer. The suspension is placed on or in the product, which is then referred to as inoculated product.
A liquid bacterial spore suspension made by a device manufacturer using a commercial, certified strain of a bacterium.
Strains of microorganisms that have been isolated from a device manufacturing facility. These strains represent the most resistant organisms found in or on the devices and are typically used for the combined BI/bioburden method of validation.

It is crucial to ensure that the type of BI used to validate or routinely monitor a given sterilization process is the most appropriate indicator for that process. In addition to identity, quantitation, resistance, storage, general directions for use, and disposal conditions, the manufacturers of BIs are required to provide information regarding the optimal culturing conditions, such as temperature and type of growth media.

Irrespective of which BI is chosen, the methods used to recover the challenge organism must be validated. This recovery is expressed in terms of the percent recovery of the original inoculum. These recovery studies can be especially challenging when using liquid spore suspensions because of the interaction between the suspension and the material onto which it is inoculated. The material substrate can alter the resistance characteristics of the inoculum because of such anomalies as spore clumping or the physical sheltering of spores in certain sites within the product.

The goal is to kill the microbes, which means disabling their ability to reproduce even in their most favorable growth conditions as described by their manufacturer. There have been records of seemingly killed microbes that regenerated when conditions become favorable.⁵ The user must validate that the incubation time under the prescribed conditions is sufficient to recover delayed growth of the organisms after exposure to a given sterilization process. For routine processing, this time period is typically 7 days unless validated for a shorter time period in accordance with current national requirements.⁶ In such cases, periodic checks should be run to confirm that the shorter time period yields equivalent recoveries to those obtained from the longer incubation period. It is also important to ensure that the incubation time is sufficient to recover growth from injured organisms exposed to sublethal cycles. In some cases, this may mean using a 14-day incubation period. This incubation period is also required by the U.S. Pharmacopeia for product sterility testing.⁷

Just as the BI must provide a defined resistance to a specified process, it is necessary to prove that the inherent bioburden on the product does not have a greater resistance than the BI. Characterizing bioburden involves quantitation, identity, and resistance of the bioburden. Several methods can be employed to determine which BI is appropriate for a specific situation.

Challenge organisms that make up BIs typically resist a particular sterilization process far more than do common bioburden organisms. The resistance of the bioburden cannot be adequately evaluated by quantitation only, yet it must be determined if the products to be processed might contain organisms that are more resistant than the challenge organism. After the microbial identifications and quantitation of the bioburden have been completed and analyzed, comparative resistance determinations of the most resistant bioburden component or product must be calculated. A literature review is also required.
When microbial identifications of the bioburden are not performed, at least one sublethal cycle should be run to compare the relative inactivation rates of the bioburden with that of the challenge organism. Product sterility testing, after exposure to at least one sublethal cycle under appropriate experimental conditions, can ensure that the product's bioburden is not more resistant than the challenge organism.
If the quantity, identity, and resistance of the product's bioburden are known, it might be possible to validate and routinely monitor the sterilization process by combining BI and bioburden methods. It must be demonstrated that the BI's degree of challenge to the sterilization process is adequate to ensure that the process will attain the desired SAL for the bioburden. Combining the BI and bioburden methods to determine the appropriateness of the BI can be time-consuming and result in additional testing costs. However, the required sterilization parameters can be more accurately determined, which can result in reduced processing time and reduced exposure to the sterilant.

BIs can be configured in many different ways depending on the cycle development method chosen.

Inoculated Product. The actual product, configured and packaged as it is intended to be sold, can be inoculated with spores of a microorganism such as Bacillus subtilis var. niger. Direct inoculation usually uses spores suspended in liquid, then placed on the product and dried. The product's surface characteristics will affect the distribution of spores and may lead to a difference in resistance behavior compared with other challenge systems.⁴ It is, therefore, important to achieve an even distribution of spores on the product's surface. Indirect inoculation involves placement of a carrier, such as filter paper that has been impregnated with spores, in the product or its package.

Inoculated Unit. A carrier, such as a filter paper strip or disk, can be inoculated with a population of a resistant organism, such as Bacillus subtilis var. niger, that has been extensively characterized and certified by the manufacturer. The resistance of this inoculated carrier must be compared to that of the inherent bioburden of the product being validated or the equivalent simulated product. An inoculated unit is usually used when there is the potential that the bioburden on the product is more resistant than the indicator organism and is required for the combined bioburden and BI cycle development method.

Inoculated Simulated Product. A simulated product that comprises the most difficult to sterilize portions of a device or that configuratively represents a device family can also be directly or indirectly inoculated. This simulated product must present the greatest challenge to the process in order to be considered an adequate microbial challenge. Each unit must contain a certified inoculum either in liquid form or on a carrier.

Natural Product. The inherent bioburden on the product can also be used as the microbial challenge during validation and for routine monitoring when the absolute bioburden method is employed for cycle development (see "EtO Cycle Development Approaches", below).

All validation methods for EtO sterilization require that the BI used for validation and to monitor routine cycles must be more resistant than the bioburden of the product and be placed in a location that is more difficult to sterilize. Comparative resistance testing is an effective means of selecting the BI and its location in the product that presents the greatest challenge to the sterilization process. Such an assessment should be made prior to validation as part of determining the appropriateness of the BI. These studies are usually carried out in small chambers that are capable of delivering rapid ramp rates, e.g., the times required to achieve specific pressure set points.

Products should be exposed to cycles in which the only variable is the gas exposure time period. The data obtained from this testing can be used to justify the choice of a specific actual or simulated product to inoculate and use for the BI. If the design of the product is such that a BI unit cannot be placed in the part of the device that is the most difficult to sterilize, the product should be inoculated with a liquid spore suspension to provide a known number of viable spores. The spore suspension, materials, and techniques used should comply with ISO 11138, parts 1 and 2.^8,9

Many device manufacturers include an additional objective in their validation plan that involves the use of external BI monitoring systems. Often referred to as process challenge devices (PCDs), they assess the lethality of the EtO process after the cycle has been designed. The PCDs are geometrically distributed around the load rather than in internal locations in the case cartons. Direct comparisons can then be made between the sterility test data obtained from these external PCDs and the BIs placed in internal locations. A PCD must be shown through comparative resistance studies to provide more of a challenge to the process when it is placed in external locations in the load than do the the BIs placed in internal locations. They usually, therefore, bear no resemblance to the product. Examples of external PCDs are spore strips double-packaged in plastic bags, in sealed plastic tubing, or in syringes. There are also commercially available PCDs that are sold as ready-to-use packaged systems. It is advisable during the validation studies to evaluate different PCD configurations during the comparative resistance studies to determine the best candidate. To monitor routine sterilization cycles, it must be shown at the time of validation that the PCDs in the external locations comply with the same requirements for resistance to sterilization.

ETO CYCLE DEVELOPMENT APPROACHES

There are three basic approaches to developing EtO sterilization cycles—the overkill method, the combined bioburden and BI method, and the absolute bioburden method.

The overkill method is probably the most widely used because it is relatively easy to use and it results in a robust SAL. The method ensures that the sterilization process will inactivate a specific number of microorganism spores known to be resistant to the EtO sterilization process. The organism most commonly used to monitor the overkill process is Bacillus subtilis var. niger. A certified preparation consisting of a stated population of Bacillus subtilis var. niger spores is inactivated through exposure to specific cycle parameters that have been assessed to be significantly higher than those required to kill the inherent bioburden on the product. The parameters are increased on a routine basis to provide the desired SAL (see "Methods for Determining Cycle Lethality," below).

The combined bioburden and BI method is used when the two are equally resistant. This method requires routine bioburden and BI testing in addition to a considerable amount of routine sterility testing to develop a cycle that will inactivate the BI challenge population. The BI must be sufficiently resistant to ensure that the EtO process will deliver the desired SAL relative to the bioburden on the product.

The absolute bioburden method is used less frequently in cycle development because it requires extensive testing in both the development phase and routine processing. However, it must be used when the product's bioburden is more resistant than the BI. Such bioburden resistance to the EtO process can be caused by any number of factors, such as the configuration of the product, the quantity or location of the microorganisms, or the bioburden's intrinsic resistance. Since the bioburden on the product constitutes the essential microbial challenge for the process, the bioburden test method must be validated and strictly controlled. The resistant microorganisms are screened through bioburden testing and may be isolated and propagated for use in cycle development studies. One negative of this method is that the microorganisms' resistance can change as a result of how they are cultured, which can adversely affect the results of the cycle development studies. The absolute bioburden method also requires extensive controls of the manufacturing environment in addition to routine product bioburden monitoring and resistance studies.

DETERMINING THE APPROPRIATE PRODUCT LOAD CHALLENGE

Microbiological performance qualification (MPQ) should be performed using specified products and packaging configured in the same manner in which they will be routinely sterilized. For the cycle to be accurate, the product load must represent the greatest challenge intended for future routine sterilization. If a device manufacturer intends to use multiple load configurations on an ongoing basis, the densest configuration should be used for the MPQ.

Each type of configuration must be documented in terms of the number of product units per case, the number of cases per pallet, the stacking patterns on the pallet, and the density. This documentation should be included with the validation data. Some testing should also be conducted on the least dense configuration, which, theoretically, presents less of a challenge to the process. This testing can be as simple as placing thermocouples throughout the least dense load on a routine cycle and comparing the temperature distribution with that of the densest load. In other cases, additional microbial challenge studies might be required. Changes in the product load must be evaluated carefully because seemingly innocuous changes, such as changing the shrink wrap or corrugate on the load, can have a significant effect on the cycle's efficacy from the perspective of product sterilization.

BI PLACEMENT IN THE PRODUCT LOAD

After the product load challenge has been identified, the BI positioning and placement can be determined. BIs should be distributed throughout the product load and, as much as possible, in the same orientation (e.g., vertical). The placement must include those locations that are considered to present the greatest challenge to the process and can be the same as those used for temperature monitoring. The ANSI/AAMI/ISO 11135-1994 standard suggests placing two BIs at each location with a temperature-monitoring device in order to obtain additional information on process efficacy. It also provides the following recommendation for the number of BIs to be included in each validation cycle:

At least 20 BIs for usable chamber volumes up to 5 m³.
Increase the number of BIs by two for every additional 1 m³ of usable sterilizer chamber volume between 5 and 10 m³.
Increase the number of BIs by two more for every additional 2 m³ of usable sterilizer chamber volume above 10 m³.

The AAMI technical information report "Contract Sterilization for Ethylene Oxide" can provide additional information on the number of BIs and monitoring devices recommended based on product load volume.¹⁰

METHODS FOR DETERMINING CYCLE LETHALITY

Results obtained from commissioning and physical performance qualification and monitoring devices should be used to identify critical features of the equipment or process that can be investigated during the MPQ. For example, it is critical that the sterilant injection time is consistent among the MPQ cycles to ensure a uniform delivery from one cycle to the next. Even minor changes in the sterilant injection time can result in significant differences in lethality.

The MPQ should be performed in the industrial chamber that will also be used for routine processing unless equivalency can be demonstrated between the industrial chamber and whatever chamber is used for the qualification. Maintaining the precise and consistent delivery of the sterilization cycle parameters is more difficult to accomplish in large industrial chambers than in small test chambers. It is also important to conduct these studies using the actual product load intended for routine sterilization. Hence, these studies are usually conducted in large industrial chambers rather than in small test chambers.

The MPQ can be performed by determining the lethality of the cycle on the basis of the number of D-values applied. The D-value is defined as "the time required to reduce a specific microbial population by 90% or one logarithm."⁴ The survivor curve construction or fraction-negative methods (described below) may be used as outlined in current standards.⁴ Another means of evaluating the MPQ is the half-cycle method, based on the number of times required to completely inactivate the BI microorganisms with an added margin of safety. The ultimate objective of each method is to determine the full cycle to which the product load must be exposed.

Survivor Curve Construction Method. The survivor curve construction method involves the direct enumeration of survivors in terms of colony forming units (CFUs) recovered after exposure to graded amounts of the sterilization cycle. A CFU is defined as "a visible outgrowth of a population of organisms arising from a single or multiple cells."² A minimum of five cycles should be run, each using different graded time exposures to EtO.⁴ The parameters used, with the exception of the gas exposure time, must be kept consistent. The first cycle is a time zero study in which the initial CFU survival count of the BI is determined by exposing the BIs to all stages of the process, including preconditioning if used, prior to the EtO injection phase of the cycle. All BIs should survive because they will not be exposed to the sterilant.

After each of the four or more additional cycles, all employing different gas exposure time periods, the number of BIs that survive the processes are counted. The BIs should be removed from the chamber and the load as soon as possible within the confines of worker exposure policies. The BIs should also be tested as soon as possible after being removed to reduce their exposure to EtO residuals, which can affect BI survival rates. In all cases, the time intervals between when the load is removed from the chamber, when the BIs are removed from the load, and when they are subjected to the enumeration process must be consistent among the cycles. Ideally, a final enumeration of the BIs from one cycle should be obtained before the next cycle is initiated to more accurately assess the exposure time to use. This is not always feasible because the enumeration process can take days or weeks to complete.

The number of BIs used in each of the cycles in the study should be statistically significant to ensure obtaining dependable data. The number can also be based on the size of the chamber or the size of the product load. The data acquired in the study are used to calculate an EtO exposure time and the minimum process parameters expected to elicit a specific probability of survival of the challenge organism expressed in CFUs (see "The Full Cycle," below). Theoretically, because all other process parameters are the same, the statistical evaluation of the data should result in a plotted survivor curve or regression analysis that demonstrates a consistent relationship between the EtO gas exposure time and the number of survivors (positive BIs). Unfortunately, this is not always the case. In addition to the issue of consistency between the BIs, the integrity of the data is dependent on the consistent delivery of the process parameters for each cycle, including precise control of gas injection times that can be considered part of the gas exposure phase for the purposes of this study. Controlling the gas injection time in large industrial EtO chambers necessitates ensuring that the head space pressure in the gas tanks is consistent from one cycle to another and that the gas delivery lines are uniformly either full or purged of gas. A few minutes difference in gas inject time can significantly change the results in this study. Other variables to consider include the temperature of the gas volatilizer, evacuation rates and times, gas makeups, and air exchanges.

If the survivor curve study is conducted in an industrial chamber, the data should elicit an accurate probability of survival of a specific challenge organism from which routine cycle parameters can be determined. The BI should be an inoculated carrier. For example, if the BI is a spore strip that contains a population of at least one million (10⁶) spores of Bacillus subtilis var. niger and the construction of the survivor curves demonstrates that total kill was obtained at 2 hours of gas exposure time, the full cycle used to routinely sterilize the product to an SAL of 10^–6 could employ 4 hours of gas exposure. To achieve a smaller SAL, for example 10^–3, would require adding the appropriate additional gas exposure time to the original 2 hours.

The BI testing process should be validated prior to initiation of the survivor curve study to obtain an acceptable and documented recovery method. The process begins with macerating the BIs in sterile water. The suspension is evaluated by plating specific dilution aliquots of serial dilutions of the suspension onto a selected agar medium and counting the number of CFUs after incubation. The number and extent of dilutions needed will be based on the duration of gas exposure and concentration in relation to the number of BI organisms. In other words, more dilutions are required when more survivors are expected.

A statistical analysis made from each cycle of survival data should show the log₁₀ of the surviving population plotted against EtO exposure time intervals. The best-fit rectilinear curve through the data can be drawn or determined by regression analysis using the method of least squares.⁸

The survivor curve method is complicated by the number of serial dilutions that must be prepared and the quality of the dilutions being dependent on the skill of the person performing the test as well as the precision of the equipment used. Only trained personnel who can adequately practice aseptic technique should conduct this test. Calibrated pipettes and dilution controls help ensure the test's accuracy. The dilutions should also be chosen to yield counts between 30 and 300 CFUs. It is generally assumed that numbers ranging from 30 to 100 CFUs should be used because it is thought that higher numbers of CFUs per plate could result in inaccurately low counts and that numbers lower than 10 CFUs per plate could give unreliable counts. For practical purposes, counts between 30 and 300 are generally acceptable.

Fraction-Negative Method. The fraction-negative method also involves exposing BIs to multiple cycles of graded exposures to EtO. The differences between the two methods are the number of cycles recommended and the number used to enumerate the survivors (in terms of the positive BIs).⁴ A minimum of seven cycles should be employed in this study, each utilizing different gas exposure time periods. These seven cycles should elicit the following survivor data:

At least one sample set that elicits all survivors (growth in all BIs tested).
At least four sample sets that elicit fractional data, i.e., a fraction of the BIs in each set demonstrates growth or survival.
At least two sample sets in which there is neither growth nor survivors.

The method used to enumerate the number of positive BIs is more straightforward than in the survivor curve method. In the fraction-negative method, the BIs are immersed directly into the appropriate media and incubated. Results are recorded in terms of the total number of BIs demonstrating growth and the total number eliciting no growth for each set of test samples.

METHODS FOR DETERMINING CYCLE LETHALITY

Calculating D-Values. The D-value corresponding to the survivor curve construction results is determined by either reading it from a graph or calculating from the data the relevant time interval for reducing the count by one log (Table I). The performance of the fraction-negative method will generate data that are then utilized to calculate a D-value using a method described by Pflug and Holcomb.¹¹ This method is also referred to as the full or generic Spearman-Karber procedure. It does not require the use of the same number of replicates nor the same gas exposure time intervals because it involves spore strips rather than counting CFUs.

Time of Exposure to Sterilant (t)	Number of Test Samples Exposed (n)	Number of Test Samples Showing No Growth (r)
t^₁	n^₁	r^₁
t^₂	n^₂	r^₂
t^₃	n^₃	r^₃
t^₄	n^₄	r^₄
t^₅	n^₅	r^₅
t^₆	n^₆	r^₆
t^₇	n^₇	r^₇

Table I. Variables used in calculating D-values during MPQ.

In Table I, t₁ represents the shortest exposure time to sterilant, and all test samples run through this short time frame should show growth. The variables t₂ to t₅ correspond to increasing exposure times in the fraction-negative area, otherwise known as the quantal region. Exposure times t₆ and t₇ should represent tests in which none of the tests show growth.

In the following equations, r₁ is the number of test samples out of the number exposed (n_i) that show no growth at exposure time t₁. For each period of exposure to sterilant t₁ to t₆, the factors x and y are calculated as shown:

At t_i, all test samples show growth, therefore,

From the calculated values of x_i and y_i above, the value µ_I(mean time to attain no growth) can be calculated for each period of exposure (t₁ to t₆) as follows:

The mean time to attain no growth from all of the test samples, µ, can be calculated from the sum of µ_I for each time of exposure t₁ to t₆:

Where the interval between exposure times (d) is constant and the same number of test samples (n) is used at each exposure time, the mean to attain no growth (µ) can be calculated from the equation:

The mean D-value (D) can be calculated from the equation:

where N₀ = the initial number of challenge organisms per test sample.

For the purposes of calculating the sterilization period using the D_calc method below, the upper 95% confidence level for D should be used. This can be calculated from the equation:

where V is derived as follows:

In addition to the method described above, there are three other commonly used means of calculating D-values. The limited Spearman-Karber procedure requires the same number of replicates for each exposure time and equal intervals between the various gas exposure times. For example, the exposure times of 9, 12, 15, and 18 minutes provide an arithmetic series of 3-minute time intervals.

The Stumbo-Murphy-Cochran procedure requires one result in the fraction-negative range, consisting of time (t), the number of units negative for growth (r) and the number of replicates (n) at each exposure time as well as the initial number of microorganisms per replicate (N₀). The D-value for each exposure time is calculated from the following equation. The confidence limits of the mean may be calculated by conventional procedures using natural logs.

The factors in the equation represent the following:

U = exposure interval.

N₀ = initial number of organisms per replicate carrier unit.

N_U = ln (n/r).

n = total number of replicate units at exposure U.

r = number of units negative for growth at U.

The D-values are averaged to obtain the overall D-value for the experiment.

The limited Stumbo-Murphy-Cochran procedure requires only one exposure time in the fraction-negative range.

It is important to choose the most appropriate procedure of the three described to calculate the D-value and its upper confidence limit. Certain methods have limitations. For example, Graham and Boris have noted that a confidence interval cannot always be determined from the Stumbo-Murphy-Cochran procedure.¹² Shintani et al. have observed that the Stumbo-Murphy-Cochran procedure can yield invalid results if r is close to n.¹³ They also state, however, that this procedure may be superior in situations in which the sample population is at least 50, r is at least 1, and r/n is less than 0.9.

Half-Cycle Method. The half-cycle method determines the minimum time a specific product load must be exposed to an EtO process to guarantee that no survivors exist from the BIs used to monitor the cycle's efficacy. The cycle chosen is based not only on the elements discussed in the companion to this article but also on the microbiological data obtained prior to determining the parameters for the half-cycle.¹ The minimum ranges of the half-cycle are based on this predetermined microbiological data, whereas the maximum ranges are dictated by the product and packaging tolerances established through functional testing.

If the half-cycle method is chosen, an additional cycle should be performed, preferably before the first half-cycle is conducted. In some cases, other proportionate cycles, referred to as sublethal or fractional cycles, may be used. The gas exposure time is shortened in order to obtain survivors from the BIs used to monitor the cycles. The process parameters in a sublethal cycle are the same as those in the half-cycle with the exception of the gas exposure time period. Such cycles are conducted to demonstrate that positive BIs can be recovered and to prove the adequacy of the BI, the sterility test method, and associated equipment and materials. The sublethal cycle is not required if either the survivor curve construction or fraction-negative method is used because these methods require positive sterility test results as part of the study.

A second objective in conducting a sublethal cycle is to attempt to demonstrate that the resistance of the product's bioburden is less than that of the BI. This is accomplished by using actual product test samples that have been manufactured, packaged, and handled in the same manner intended for routine production. It is imperative that these test samples were made in accordance with routine manufacturing procedures because the bioburden on the product must represent what the product would normally contain. Sometimes using a number of different product samples can yield useful information when there is concern about not only the quantity of bioburden but also where it is located. If a number of different samples have been sterility tested, those with the highest bioburden should be used for validation. After the completion of the sublethal cycle, the product samples are sterility tested. Since the objective of the test is to demonstrate sterility of the bioburden, the data can be compared to the positive sterility test results obtained from the BIs to demonstrate that the resistance of the product's bioburden is less than that of the BI.

A third objective of the sublethal cycle study is to determine that a PCD used as an external monitoring device for routine sterilization cycles yields more positive sterility tests than an internal BI does. It has been suggested that it is acceptable to obtain positive sterility test results from those external PCDs exposed to the half-cycles if previous comparative resistance studies have proven that they are as resistant or more resistant than the internal product BI and if no positive sterility test results are obtained from the BIs placed in internal load locations. If total kill is obtained from all PCDs on all half-cycles, it can be assumed that the resulting validated full cycle will provide an additional safety factor that goes beyond the minimum requirements.

Typically, the sterilization efficacy of the first half-cycle is determined before any subsequent cycles are conducted. If the first half-cycle experiment elicits all negative BIs, two additional half-cycles are conducted to confirm the data. All three half-cycles must employ the same parameters to demonstrate reproducibility and reliability. All three half-cycles must demonstrate the ability to elicit all negative BIs. If a SAL of 10^–6 is required, a gas exposure time that is at least double that used in the half-cycle becomes the minimum gas exposure time used routinely in the full cycle.

THE FULL CYCLE

The data obtained from the survivor curve construction method, the fraction-negative method, or the half-cycle method are used to design the full cycle that will be used to routinely sterilize the product. The full cycle must be capable of reliably demonstrating a required SAL that consists of the minimum time to obtain all negative BIs or CFUs with an additional margin of safety. Normally this can be expressed as 10^–n where n is the cumulative probabilities of the log minimum time to sterilize and the log margin of safety. For example, if the half-cycle method was chosen to validate a given sterilization cycle with a required SAL of 10^–6, the half-cycle must demonstrate the ability to ensure that there are no survivors from BIs that have a certified population of 10⁶. Since the BIs have a greater resistance than the product bioburden, it can be concluded that the time is sufficient to achieve product sterility. However, adding an equivalent sterilization time period increases the margin of safety. The additional 6 log reduction in the population (10^–6) is theoretical and is obtained by doubling the half-cycle gas exposure time. In other words, if the half-cycle gas exposure time period was 2 hours, the full-cycle gas exposure time would be a minimum of 4 hours.

The processing ranges established for the critical parameters in the full cycle should be based on the ranges determined in the half-cycle. The minimum process parameters in the full cycle, such as temperature, sterilant concentration, pressure, and humidity, may also be greater than those used in the half-cycle to ensure greater lethality with the full cycle. The first full cycle should be included in the validation to complete the profile of the product load. The same type and amount of monitoring should be conducted during the first full cycle as was conducted on each of the half-cycles. Comparisons of temperature distribution throughout the chamber and the load can justify a determination of reliability and repeatability for the process. These data can also be useful for determining the significance of any minor changes that are made to the load.

REPORT ON VALIDATION AND CERTIFICATION

The documentation on the validation and certification should include but not be limited to the following:

References to the maintenance and calibration procedures for the processing equipment.
Specifications for the EtO chamber.
References to the commissioning data.
An indication that all gauges, monitoring devices, etc., were calibrated prior to initiation of and at the conclusion of the validation.
The validation protocol.
Comparative resistance test data and reference to the protocol.
A complete description of the products used as test samples, including packaging.
BI certification and all data, according to current standards, required in the labeling.
The physical and biological records from all of the validation cycles.
Placement diagrams and data for the monitoring devices (including temperature, gas concentration, and relative humidity).
Documentation on and verification of the positioning and location where the BIs and product test samples were placed on the product load.
BI population determination test results and statement of retention samples.
All biological test data associated with the validation.
EtO residual test data.
References to the test procedures used during the validation.
Documentation of operating procedures, including process control limits.
A test report summarizing and analyzing the validation data.

ANNUAL REVALIDATION

An annual revalidation of the process should be conducted to verify the integrity of the original validation data. It may be advisable to conduct this revalidation within 13 months of the initial validation and each year thereafter until sufficient data are obtained to allow that time period to be extended. Afterwards, revalidation should be conducted at least every 2 years.

Data from each revalidation should be compared with that from the original validation and any subsequent revalidation to confirm that the original performance specification remains valid. A revalidation consists of a thorough review of all the factors that could affect the sterilization process, including changes to the product or its packaging, the manufacturing methods and facility, and component and materials suppliers. Product bioburden test data should be analyzed and trends noted to ensure that there have been no substantial unacceptable changes in quantity or characterization. The testing conducted of the preconditioning room, the sterilization chamber and ancillary equipment, and the aeration room and equipment should be compared with the data obtained during the original validation as well as to the commissioning data. All associated programs, such as preventive maintenance and calibration, should be reviewed for effectiveness.

CONCLUSION

A well-designed and scientifically sound MPQ helps ensure that the process is safe, efficacious, and efficient. Performed well, the MPQ should deliver the required SAL for the product in an economical process and should enable the process to continue without having to be repeated. It should also prevent product reprocessing and delays in product release to the marketplace. A knowledgeable approach that considers all of the various aspects of the MPQ will ensure the success of the process.

ACKNOWLEDGMENT

The authors would like to express their gratitude to Aubrey S. Outshoorn, PhD, of the United States Pharmacopeial Convention Inc. for his contributions to this article.

REFERENCES

1. PJ Sordellini and SE Satter, "EtO Sterilization: Principles of Process Design," Medical Device & Diagnostic Industry 20, no. 12 (1998): 47–59.

2. "Sterilization of Medical Devices—Microbiological Methods—Part 1: Estimation of Population of Microorganisms on Products," ANSI/AAMI/ISO Standard 11737-1 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1995).

3. "Guidance on the Application of EN 29001 and EN 46001 and of EN 29002 and EN 46002 for Non-Active Medical Devices," BS/EN 724 (London: British Standards Institution, 1995).

4. "Medical Devices—Validation and Routine Control of Ethylene Oxide Sterilization," ANSI/AAMI/ISO Standard 11135 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1994).

5. EW Nester et al., Microbiology, 2nd ed. (Chicago: Holt, Rinehart, and Winston, 1978).

6. The Center for Devices and Radiological Health, FDA Guide for Validation of Biological Indicator Incubation Time (Rockville, MD, FDA, 1985).

7. United States Pharmacopeia 23, 8th supp., monograph <71>, 1998.

8. "Sterilization of Health Care Products—Biological Indicators—Part 1: General Requirements," ANSI/AAMI/ISO Standard 11138-1 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1994).

9. "Sterilization of Health Care Products—Biological Indicators—Part 2: Biological Indicators for Ethylene Oxide Sterilization," ANSI/AAMI/ ISO Standard 11138-2 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1994).

10. "Contract Sterilization for Ethylene Oxide," AAMI TIR no. 14-1997 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1997).

11. IJ Pflug and RG Holcomb, "Principles of Thermal Destruction of Micro-Organisms," in Disinfection, Sterilization and Preservation, ed. SS Block, 3rd ed. (Philadelphia: Lea and Febiger, 1983).

12. GS Graham and CA Boris, "Chemical and Biological Indicators," in Sterilization Technology: A Practical Guide for Manufacturers and Users of Health Care Products (New York: Van Nostrand Reinhold, 1993).

13. H Shintani et al., "Comparison of D₁₀-Value Accuracy by the Limited Spearman-Karber Procedure (LSKP), the Stumbo-Murphy-Cochran Procedure (SMCP), and the Survival-Curve Method (EN)," Biomedical Instrumentation Technology 29, no. 2 (1995): 113–124.

Review of surface steam sterilization for validation purposes.

2010-09-29T11:19:00.000-07:00

Sterilization is an essential step in the process of producing sterile medical devices. To guarantee sterility, the process of sterilization must be validated. Because there is no direct way to measure sterility, the techniques applied to validate the sterilization process are based on statistical principles. Steam sterilization is the most frequently applied sterilization method worldwide and can be validated either by indicators (chemical or biological) or physical measurements. The steam sterilization conditions are described in the literature. Starting from these conditions, criteria for the validation of steam sterilization are derived and can be described in terms of physical parameters. Physical validation of steam sterilization appears to be an adequate and efficient validation method that could be considered as an alternative for indicator validation. Moreover, physical validation can be used for effective troubleshooting in steam sterilizing processes.

Sterility testing of antimicrobial-containing injectable solutions prepared in the pharmacy

2010-09-27T05:50:00.000-07:00

The need for sterility testing of antimicrobial-containing injectable solutions is discussed and specific testing methods are described. Despite their antimicrobial activity, antimicrobial-containing injectable drug products are not necessarily self-sterilizing and can become contaminated. In addition to practicing aseptic technique, pharmacists must perform end-product sterility testing on intravenous solutions to ensure their sterility. The United States Pharmacopeia provides guidelines for the performance and validation of two sterility test methods: membrane filtration and direct transfer to culture media. Membrane filtration is the method of choice for sterility testing of many antimicrobial-containing injectable solutions. After the test article is filtered, the membrane is rinsed with sterile fluid to remove residual antimicrobial agent, cut into two portions, and immersed in two types of culture medium. Visible turbidity of a sample within the appropriate incubation period indicates the presence of a contaminating microorganism. Closed filtration systems minimize false-positive results. In the direct transfer method, samples of the test article are directly inoculated into vessels of culture media, and antimicrobial activity is eliminated by dilution or by deactivation with chemical or enzymatic agents. Sterility testing as well as aseptic technique is needed to ensure the sterility of antimicrobial-containing injectable solutions.

DQ, IQ, OQ, PQ FOR BIOMETRIC SYSTEM

2010-09-26T02:01:00.001-07:00

1.0 DESIGN QUALIFICATION
1.1 Define the Biometric Technology Used. It’s Principle and Capturing System. E. g

1.2 Define the Extraction and Comparison Process
Specify how the system will extract the captured data and convert into mathematical Code /template for comparison purpose.
Specify the threshold value for the purpose of comparison.
1.3 Define Vendor Qualifications for Biometric System.
- Number of Biometric System installed.
- Types of the technology used.
- Type of post marketing feed back received by him.
1.4 Define Final Specifications and Acceptance Criteria agreed between Vendor and User.
- Technology to be used.
- Capturing device to be used.
- Extraction and Comparison system to be used.
- Threshold value for the match.
- Maximum Failure rate (False Rejection, False Acceptance) per day.
2.0 IQ FOR BIOMETRICS
2.1 Check the computer system where it will be installed.
- Check the drive.
- Check the space required.
- Check the ancillary softwares required on Computer.
- Check the power supply.
- Check the dust controls procedures used in the room where system is to be installed.
- Check whether the system meets the agreed specifications.
3.0 OPERATIONAL QUALIFICATION
3.1 Define the SOP for Biometrics.
3.2 Check the password, which may be required to activate the system.
After activation check if the system is ready to scan, extract and compare the specified biometric feature.
3.3 Check for operation manual, maintenance, and calibration manuals.
4.0 PERFORMANCE QUALIFICATION
Try excess to the computer system by exposing required biometric feature to the machine
Record the results as per follows

Please Note
Specify the conditions of scanner plate during PQ ( It should be free from dust and smudges.
Specify integrity of biometric feature (The body part which is used by the system shall be intact. It shall not be cut, bruised, or damaged. For Example, if entire Finger is used, it shall not have cuts).
5.0 ACCEPTANCE CRITERIA
- Failure to activate the screen : Nil
- False Rejection : Nil
- False Acceptance : Nil
6.0 VALIDATION REPORT
- Describe the DQ, IQ, PQ, and OQ briefly.
- Describe the SOP followed for PQ
- Compare the results against the acceptance criteria.
- Conclude – System is satisfactory. System needs improvement and revalidation.
7.0 SOP’S for the Biometric System based on Finger Technology.
• Activate log on screen.
• Check the scanner plate.
• Clean it if there is smudging.
• Clean the left index finger, wipe it dry and expose the required area/ part to scanner plate.
• Wait for response.
• If allowed, proceed with you work.

DQ,OQ PQ FOR COMPUTER SYSTEM

2010-09-26T02:00:00.001-07:00

1.0 Define the System

1.1 Describe the purpose.

- Analytical Use.

- Inventory / Store.

- Archives / Records.

- Management Information.

1.2 List of all Hardware.

1.1 List all Softwares.

1.4 List all Operational Parameters.

1.5 Define Requirements to Operator.

1.6 Define Security Requirements.
- Hardware Lock
- Password Access.
- Biometric.
- Hardware Lock + Password Access.
1.7 Check following parameters concerning to DQ
- Purchase Order.
- Certificates and specifications for Vendor.
- Communications between internal users and Vendors.
- Users Manual.
- Maintenance, Calibration, and testing guidelines.
- All Drawings.
- List of Spares Supplied.
1.8 Check following parameters concerning OQ.
- Date of Installation.
- Installation Report.
- Place of Installation.
- Power Supply.
- Safety aspects.
- Calibration Details.
- Functionability of all switches and ancillary devices such as Printer, Modem, LAN, FDD, ZDD.
1.9 Verify following matter concerning PQ
- Security System.
- Operator Qualification.
- Functioning of each module and functioning of the total system over anticipated operating range.

VALIDATION REPORT
Prepare Validation Report stating Acceptance Criteria and Observations.

CONCLUSIONS
- System was valid during its past use.
- System was not valid during its past use and performance may have errors.
- System was not valid and needs improvement.
- System has become outdated and may be dissolved.

PQ: DATA MIGRATION

2010-09-26T01:59:00.001-07:00

1.0 Define the inventory of Old Data

- Computer system where the data is located.

- Format of data.( Text, Graphics).

- Data Volume (MB, GB).

- Identify the Raw Data Formats used.

- Identify the different files and their contents.

2.0 Define the Importance of Data

- Archiving is compulsory under regulatory requirements.

- Data will need reanalysis / Recomputing in future.

- Data is required very often by many users.

3.0 Define the Old and New Computer System involved in Data Migration.

- Hard Disc Capacity.

- A/D Device Used.

- Operating System Used.

- Associated Softwares, their vendor and versions.

- RAM

4.0 Experimental

Select the critical files from the old computer and migrate the same to new computer system and check the result.

VALIDATION REPORT

The entire data was identified by its File Number, format, and Volume. The critical text and values were underlined.

After migration, all documents were checked for correctness by designated persons. There were no change in formatting and Volume. The critical values, graphs were not affected by any means. The transfer was complete in respect of raw data, meta data, and processed data. The data can be accurately archived and processed on new system and the results are within the limits as specified during the original computation.

VALIDATION FOR COMPUTER SYSTEM

2010-09-26T01:58:00.001-07:00

1.0 What is Computer Validation?

The Food and Drug Administration of the USA defines Validation as

“Establishing documented evidence that provides a high degree of assurance that a specific (computerized) process will consistently produce a product meeting its predetermined specifications and quality characteristics”.

To simply put it: Identifying and documenting that the computer system does what it is supposed to do consistently, repeatedly, and accurately.

2.0 What comprise the Computer System?

A device made up from electronics that can store and run a software-coded program. This includes all microprocessor based controllers, PLC, SCADA Systems, DCS, ERP, LIMS etc.

3.0 Why is Computer System Validation required?

RISK

Risk associated with the patient’s life being one of the most critical followed by Risk associated with the product quality. Risk associated to Goodwill and thus Risk associated with the business.

4.0 What are Regulatory Norms?

It is required to validate the Computer System especially by the regulatory bodies of Europe and USA. Even the MCC, TGA, Japanese regulatory bodies have recommended computer system validations. Any exports to the countries in these jurisdictions will want the computer systems validated.

5.0 What are Advantages of Computer Validation?

Helps in keeping track of the performance of the computer system implemented in the organization. It also helps in perfecting the system and making it devoid of any bugs or errors.

6.0 Difference between Equipment Validation and Computer System Validations?

The major difference between the Equipment Validation and Computer System Validation is that the computer system validation begins at the beginning of the system design. It begins and goes through a complete SDLC (System Design Life Cycle). The computer system validation begins with freezing the URS (User Requirement Specifications) and ends with the Performance testing of the system and further plans on decommissioning.

1.0 How to perform Computer System Validations?

New Systems Validation (Module I)

7. On conceptualization of a computer system it is very important to create a URS in a very simple language and is conveyed by the actual user. Each URS should be unique and clearly defined and testable and unambiguous. No conflicting requirements should be asked for. Many a times it may so happen that the end user is qualified enough to describe the functional requirements of the system as well. Based on the URS the technical team creates a functional requirement specifications (FS) detailing the functional aspects of the system. On the basis of URS and FS the detailed Design Specifications (DS) are made. Design Specifications equivalent to Design Qualification. On completion and approval of DS the inquiry is floated to all the listed vendors who can fulfill the requirements and separate Vendor Audits Performed. It is very necessary to conduct this audit with the view of after sales support, support in validation of System, vendors past record, infrastructure, willingness to create a Escrow account and many such factors. Evaluate the vendor for the quality Management System with him. The commercial contract should be signed only after Vendor management and qualification is approved.

A whole lot of documentation should be called for before placements of Commercial order, which are ultimately required for the Validation of Computer systems.

Third party agencies (like Vaiktron) re available to undertake Vendor Qualifications or the Computer System Validations.

VALIDATION OF LAN SYSTEM - DESIGN PARAMETERS

2010-09-26T01:57:00.002-07:00

1.0 DESIGN PARAMETERS
1.1 Define the Lan Model
The Open System Interconnection (OSI)
Others
1.2 Define the various protocols used
The Physical Layer
Transmits raw data bits over a communication channel (mostly mechanical and electrical issues)
The Data Link Layer
Guarantees to the network layer that there are no transmission errors by breaking the input data stream up into frames and sending back acknowledgement frames
The Network Layer
Controls the operation of the involved subnet; main issues are routing (determine a way from source to destination) and dealing with problems of heterogeneous networks, e. g. different size requirements of transmitted data blocks
The Transport Layer
Splits up data from the session layer if necessary (segmentation) and ensures that the pieces arrive correctly
The Session Layer
Allows users on different computer systems to establish a session between them, i. e. they are able to transfer files or log into a remote system; the conditions of communication are laid down, for example full-duplex or half-duplex
The Presentation Layer
Unlike the layers before it is concerned with the syntax and semantics of the transmitted information; it is concerned with all aspects of information representation such as data encoding, data compression and encryption
The Application Layer
Contains a variety of commonly needed protocols like handling with different terminal types and file systems; a label to identify the communication process, its origin and destination application is added to the transmitted information
Define true end-to-end layers, i. e. the layer on the source system carries on a communication process with the same layer on the destination system.
Define the other layers i.e. the lower layers wherein the protocols are between a system and its immediate neighbor
1.3 Define Medium Access Control (MAC) sublayer, which determines how the devices are attached to the network.
1.4 Define the intended speed of computer networks. The speed is measured in terms of the amount of information units (bits) that can be transmitted per second. Often, to transmit one character of a text, eight bits are necessary. Thus, if a network would have a speed of 8 bits per second (bps), one character per second could be transmitted. The speed of real networks is much higher. Usually Kilo, Mega, and Giga bits per second are common measures (Kbps, Mbps, Gbps), which mean thousands, millions or billions of transmitted bits per second.
1.5 Define the intended speed for running individual application softwares
1.6 The topology of a network (representation of how the devices in this network interact)
- Bus topology
- Ring topology
1.7 Define the transmission media used
Twisted pair
Two insulated copper wires twisted together in a regular spiral pattern; one pair establishes one communication link; it transmits electromagnetic signals. Twisted pairs are distinguished between shielded and unshielded twisted pairs according to their protection against electromagnetic fields
Coaxial cable
A single insulated inner wire is surrounded by a cylindrical conductor which is covered with a shield; it transmits electromagnetic signals. Coaxial cable is classified into two categories: base band (uses digital signals) and broadband (uses analog signals) coaxial cable
Optical fiber
Consists of three concentric sections, the core (a fiber conducting optical rays), the cladding (reflecting optical rays) and the jacket (surrounding one or many fibers to protect them); transmits optical signals, which must be transformed to electromagnetic signals
1.8 Defining Objectives
Define what the system is supposed to do. This should be as quantitative as possible and related to the creation, storage, transfer, and processing of information. The goals must be based on the present situation, which can certainly be improved. The whole environment of the planned system should be looked at; there should be no restrictions at that point of the process. This leads to some key product goals from which more specific system requirements can be derived.
1.9 Determine Communication Needs
Explain how information has to be moved what the network has to do. Network requirements have two major points: compatibility (the possibility to connect the devices) and capacity (maximum performance of the net). Thus, the selection of a network should take into account interconnection with other networks and future growth of the network.
1.10 Define other objectives
The network has to meet the established requirements and to provide the needed services
- Network must be expandable with only incremental costs
- Network is reliable (total network failures are prevented)
- Network can handle equipment supplied by several vendors
- Ease of installation, maintenance, reconfiguration, interconnection
- Software availability
- Limited Access capability
- Biometrics
- Data Migration and Archiving from one computer to the other
- Software access from multi-user versions of the software
- Audit trail
- Read Only/Read and Edit features
- Electronic Time
1.11 Correct storage retrieval Meta data
1.12 Communication with Printer,
- Scanner and other peripheral
- Devices for all points
1.13 Correct Function of special Application Software for all USERS

VALIDATION DURING SOFTWARE DEVELOPMENT

2010-09-26T01:57:00.000-07:00

Validation of softwares during development is performed in three distinct stages:

1. Validation of Design Inputs

2. Validation of the Implementation stage

3. Validation of Alpha and Beta Testing

1.0 VALIDATION OF DESIGN INPUTS

1.1 Design Specifications

Prepared By : ________________

Approved By : ________________

Design Checked By : ________________

1.2 Validation Report

This shall include

a. Internal Design Document.

b. Report on Design Inspection in above format.

c. Comments e.g. whether Design Specifications are complete, correct, and consistent with the defined requirements.

2.0 VALIDATION OF IMPLEMENTATION PHASE

2.1 Validation Report

This shall include

a. Description on Source Code and Internal Documents used.

b. Report on Functionability and reliability of individual and group programming.

3.0 ALPHA TESTING

3.1 Inputs

3.1.1 Test cases Prepared By : QA Person.

3.1.2 No. of Test Persons : 10 - 20

3.1.3 Type of the information

provided to the Persons : Detailed Test Description and Expected Results.

3.2 ALPHA TEST SUMMARY SHEET

The test results are evaluated Graphically. The defect Discovery Rate plotted versus the Total number of Defects Discovered. A regression linear fit curve is calculated and plotted together with maximum and minimum fits, which by definition have a confidence interval of 5%. This helps in calculation the number of remaining defects. This information is useful to forecast the number test cycles that are still necessary and a possible release date.

The number of critical defects after the last test cycle must be zero for the software to pass the release criteria.

4.0 Beta (b) Testing

Once software defects and usability discrepancies reported during alpha testing have been corrected, the software may be tested at selected customers’ sites (the so-called b- test). The key feature of b-testing is that it is conducted in a customer environment and supervised by a person not involved in the development process. One of the objectives of b -testing is to test the HP Product delivery and support channel. A trained HP applications engineer (AE) assists the customer with installation and checks the software installation procedure.

4.1 Validation Report include:

Test plans with acceptance criteria and test cases

Test results

Validation documents

Defects density report.

User Training Material

System status bulletin (SSB)

Sunday, August 8, 2010

VALIDATION OF LAN SYSTEM - PERFORMANCE QUALIFICATION

1.1 Data Access
Prepare Test cases with slightly distrtal combination of Login ID and password and attempt access.
Designated ID

1.2 Audit Trail
1.2.1 File to be checked :
1.2.2 Persons having access :
1..2.3 Data

1.3 Communication with Peripheral

1.3.1 Peripheral to be checked -Printer :
1.3.2 File to be checked :
1.3.3 File Size :

2.4 Data Integrity

Validation in pharmaceutical analysis

2010-09-25T07:39:00.000-07:00

The ICH guidelines achieved a great deal in harmonising the definitions of the required validation characteristics and their basic requirements. However, they provide only a basis for a general discussion of the validation parameters, their calculation and interpretation. It is the responsibility of the analyst to identify parameters which are relevant to the performance of the given analytical procedure as well as to design proper validation protocols including acceptance criteria and to perform an appropriate evaluation. In order to fulfil this resposibility properly, the background of the validation parameters and their consequences must be understood. In this part, the general concept of an integrated validation is discussed. The interdependencies to other ICH guidelines and topics during drug development (e.g. impurities and degradants, stability and specification design) must be taken into account to define the required acceptance criteria. Evaluation of the results in order to prove the suitability of the analytical procedure must be based on the specification limits. Important parameters and aspects are discussed for the individual validation characteristics. In the following parts, these parameters will be discussed in detail. Examples will be given for their interpretation in order to facilitate the selection of parameters which are relevant to the performance and suitability of the given analytical procedure.

Author Keywords: Pharmaceutical analysis; Validation; Quality assurance; Acceptance limits; Specification limits

Thermal Validation in the Pharmaceutical Industry

2010-09-25T07:36:00.000-07:00

Considerations in Selecting a Temperature Sensor

The pharmaceutical industry is a highly regulated environment based on research, evidence, record-keeping, and validation. The term "thermal validation" is the process of validating / qualifying equipment and storage facilities to prove that they will create and maintain the temperatures they are designed for.
For those responsible, choosing the right temperature validation tool is decision #1 - and making that choice requires a thorough understanding of different sensor types. This paper will specifically focus on two common sensors: thermocouples and thermistors (see table below).
The following article will discuss the advantages and disadvantages of each sensor, especially as they are used in the pharmaceutical industry. But first, a brief definition of thermocouples and thermistors:

A thermocouple is made of two dissimilar metals in contact with each other. The thermocouple works by generating a small voltage signal proportional to the temperature difference between the junctions of two metals.
A thermistor is a resistive device made up of metal oxides that are formed into a bead and encapsulated in epoxy or glass. As temperature changes, so does resistance, causing a large voltage drop.

The follow table describes the stability, temperature ranges and gives brief details about the differences between thermocouples and thermistors.

	Thermocouple	Thermistor
Temp. Range	-270 to 1800°C (-454 to 3272°F)	-86 to 150°C (-123 to 302°F)
Sensitivity	Low	High
Stability	Low	High
*Time-savings	Lengthy set-up	Minimal set-up
*Sources of Error	Many	Few
*Accuracy	Low	High
Ideal Applications	High temperature oven profiling, Cryogenic freezing	Warehouse monitoring, Stability testing, Chamber qualification, Cooler and Freezer, Monitoring, Lab monitoring, Cold Chain monitoring.

* This comparison looks at a total data logging system, and not just the sensor.

Temperature Range: The Key to Selecting Sensors

Thermocouples offer the widest range of measuring capabilities, which admittedly makes them a suitable choice for extreme temperature applications such as oven profiling and cryogenic freezing.
However, in the range of -86 to 150°C (-123°F to 302°F), thermistors become an option, and for most applications they are the better choice. Thermistors are primary sensors, meaning that they operate independently, without the need for a second reference sensor.
It is important to note that other systems, including thermocouple systems, often use thermistors as the reference sensor.

Data Loggers & Temperature Sensors

The stated temperature range of -80 to 150°C (-123°F to 302°F) is just for the thermistor itself, and not for an enclosed Veriteq data logger. Veriteq data loggers are designed to withstand the range of -86 to 85°C (-123°F to 185°F) meaning that the loggers themselves can be placed in the temperature environment and left there. This makes them an ideal solution for chamber qualifications, stability testing, warehouse, cooler and freezer monitoring.
Veriteq's data logger used in the higher range of 85°C to 150°C (185°F to 302°F) requires an external thermistor probe that allows the connected logger to remain outside the high temperature environment.

Sensitivity: Of Voltage & Signal Size

The term sensitivity refers to the size of signal received in response to a temperature change, and is an important component of sensor accuracy. Thermistors are highly sensitive; in fact the name thermistor evolved from the phrase "thermally sensitive resistor."
Stuart Ball, an electrical engineer and author for www.embedded.com writes that "of all passive temperature measurement sensors, thermistors have the highest sensitivity."
In comparing thermistors with thermocouples, Ball goes on to say: "The voltage produced by a thermocouple is very small, typically only a few millivolts. A type K thermocouple changes only about 40 microvolts per 1°C (1.8°F) change in temperature."
With such a minute voltage to measure, it becomes difficult to distinguish an actual temperature change from noise. Enercorp Instruments Ltd., a provider of thermocouples and thermistors, speaks directly to this issue:

"The voltage produced is very small and amounts to only a few microvolts per degree Celsius. Thermocouples are therefore not generally used within the range of -30 to 50°C (-22 to 122°F)."

The graphs below show the increased sensitivity that a thermistor-based system detects as compared to a thermocouple system.

Stability: How Accurate for How Long?

Thermistors are very stable, which makes them ideal for portable applications such as warehouse and chamber qualifications. For example, Veriteq data loggers can be moved frequently without calibration, and still maintain an accuracy of +/- 0.15°C (+/-0.27°F).
To prove the point, Veriteq recently checked the calibration of 106 data loggers after a year of use in the field. Each logger was checked at the following calibration points: -20°C, 25°C, and 70°C. The results were impressive, showing less than 1% of the points to have any excess drift. Still, Veriteq recommends that data loggers are re-calibrated on a yearly basis.
Thermocouples, on the other hand, are known for low stability, which is why a pre-cal / post-cal is required with every use.

When a Sensor Saves Time: Set Up & Stability

A Veriteq data logger is a system in itself,easy to use, quick to set up and self powered. With on board memory, the data is not vulnerable to loss through power or network interruption.
Each data logger, containing a thermistor, is simply configured to the desired sampling frequency and then placed in the monitoring location. Following the test period, the data is downloaded. The system is very straightforward and doesn't require any stringing of wires. Validation without stringing thermocuouple wires reduces set up time and downtime in a high-traffic environment. The result is a significant time savings.
By contrast, a thermocouple based set-up is often time consuming, especially for high-accuracy applications requiring a pre- and post-calibration. For example, qualifying a chamber with a thermocouple system involves first putting all sensor ends (i.e. the hot junctions) inside a calibration unit and going through the pre-calibration process.
Following a successful calibration, the thermocouples are strung from the central data logging unit, to the chamber, through a door seal, and then taped into various positions. Care must be taken to keep a good seal on the door while minimizing damage to the thermocouple wire.
Once the data collection begins, all thermocouple sensors must still be moved to the calibration unit for post-calibration. Finally, it is not uncommon for thermocouples to fail the post-calibration, meaning that the whole process may need to be repeated.

Sources of Error: Cold Working, Cold Junctions, Calibrations

Being a self-contained unit means that Veriteq data loggers have less error sources to deal with - there are no wiring errors, no cold junction errors, and no errors associated with in-field calibration (see table below).

	Thermocouple System	Veriteq Thermistor System
Physical damage to sensor	"Cold working" degrades thermocouple wires as they are repeatedly bent, stepped on, or shut in chamber doors.	There is minimal risk because the thermistor sensor is protected inside the data logger
Non homogeneity Consistency of thermocouple wire and the environment it runs through	Always present to some extent	N/A
Cold Junction reference error Temperature deviation between cold junction reference point and the actual cold junction; includes accuracy of cold junction sensor	The single largest source of error	N/A
Pre & post calibration errors: Reference transfer calibration error; traceable temperature standard; environmental stability; movement of sensors	In-field calibration introduces many sources of error	Pre & post calibration is not required
Operator Error	High level of knowledge required to minimize errors	Less risk as the system is relatively simple
Analog to Digital conversion	Minor	Minor

Thermocouple systems have numerous sources of error, the most significant being the cold junction reference error. Goran Bringert, of Kaye Instruments, states the following:

"A change in ambient temperature is the most significant source or error in thermocouple measuring systems, particularly multi-channel systems with internal cold junction references"

Accuracy: Give or Take a Margin of Error

High accuracy is critical for temperature validations because of the 4:1 rule, which recommends that instruments be at least four times as accurate as the parameter being measured/validated. Therefore, Veriteq data loggers, with their accuracy of ±0.10°C (±.27°F), can be used to monitor/validate parameters as tight as ±0.60°C (±1.1°F).
As for thermocouple based systems, a leading provider claims to have a total system accuracy of ±0.28°C (±0.5°F). While this may be true from a theoretical point of view, it would require having optimal conditions available.
Other industry experts believe that ±1 to 2°C (±1.8 to 3.6°F) is a more realistic accuracy for such a system, meaning that it could be used to validate parameter specifications of ±4 to 8°C (±7.2 to 14.4°F), applying the 4:1 rule. In any event, very few people dispute the fact that thermistors are more accurate than thermocouples.

Conclusion

When choosing a system for performing thermal validations, the first question asked should be "what kind of sensor is being used?"
Thermocouple sensors should be avoided because they involve a lengthy set-up, numerous error sources, and marginal accuracy. It would be best to restrict thermocouple systems to applications involving very high or very low temperatures, simply because there are no other choices available at those extremes.
In contrast, thermistor sensors are ideally suited to high accuracy monitoring in the range of -86° to 150°C (-123°F to 302°F). The Veriteq thermistor based system is highly sensitive, stable, accurate and easy to use.
Using a thermister-based device for validation eliminates the many error sources associated with thermocouple systems and allows for a much quicker set-up time. In short, you save time, experience less downtime and obtain high-accuracy results.

V Model Validation Process-in the Pharmaceutical Industry - FDA Perspective

2010-09-25T07:34:00.000-07:00

Summary
The objective of this paper is share Conceptual clarity while working on Life science SAP projects ( End to end, Solution Rollout, Development & Support etc) and try to take best practices out of this to other domain projects. To bring the importance of Validation, Compliance from Quality System point of view.
Author: Girish Deshpande
Company: Satyam Computer Services Ltd
Created on: 30 December 2008
Author Bio
Girish Deshpande has worked in leading Automobile manufacturing for eight years in area of Quality Assurance and has extensively worked as Senior Consultant in Quality Management, Plant Maintenance, and Document Management System for global clients in Pharmaceuticals giants in Europe, Steel Manufacturing units, Beverage bottler in China from eight years. The aim of this paper is to share V model & validation in Pharma from FDA point of view.
Table of Contents
Introduction ........................................................................................................................................................ 3
GxP Overview .................................................................................................................................................... 3
Key Regulatory Bodies................................................................................................................................... 3
What is CSV (Computer System Validation)................................................................................................... 4
V Model Concept ............................................................................................................................................ 6
Validation Process ......................................................................................................................................... 6
Document Tractability .................................................................................................................................... 7
Conclusion ......................................................................................................................................................... 7
Related Content ................................................................................................................................................. 7
Disclaimer and Liability Notice .........................................................................................................Introduction
The primary aim of this article is to share key concepts while one work with Life science SAP projects in particular to Pharmaceutical, Beverage, and Health care domain. Under stand and implement universally formed model while executing projects. Following are key theme
 GxP overview
 Know Important Regulatory bodies
 V model
 Importance of Validation
 Document Tractability
As most of you know that entire Pharmaceutical Industry (Finished goods, Intermediate products, Drugs & Substance manufacturing) deals with human & animal life, saving human. The pharmaceutical industry undertakes the development, production and supply of pharmaceutical products needed to save lives, prevent disease and otherwise assist in maintaining quality of life.
This industry is governed by Regulatory authorities and lot of emphasis on documentation. There is huge Research & Development investment with long lead time for product to come into market for commercial purpose once regulatory approvals are in place.
GxP Overview
The term GxP means GMP ( Good Manufacturing Practices) „x‟ includes
 GCP ( Good Clinical Practices )
 GLP ( Good Laboratory Practices )
 GDP ( Good Distribution Practices )
The pharmaceutical industry is regulated industry means pharmaceutical. Preparations must be safe and effective for patients & the general public. It must protect consumer. Adhere to GxP for compliance & Proof that any systems and activities are “fit for purpose”.
In nutshell the GMP covers all business functions which are closely associated with business process in major category People who follow certain Processes to make required Products with the help of administrative, Quality, regulatory Procedures & related paper work.
Key Regulatory Bodies
In major continents across globe, we have International reputed agencies who has worldwide presence who acts as Regulated bodies for Pharmaceuticals industry
 Food & Drug Admirations (FDA) –Relevant for US Market mainly
 European Medicines Evaluation Agency (EMEA) –For European Region
 Drug Controller General of India –For IndiaWhat is CSV (Computer System Validation)
 Computerized system validation (CSV) is the documented process of assuring that a computerized system does exactly what it is designed to do in a consistent and reproducible manner.
 The validation process begins with the system proposal / requirements definition and continues until system retirement and retention of the e-records based on regulatory rules.
 System definition artifacts that reflect these requirements can include, but are not limited to, the following:
o User Requirements Specification: What the system needs to do for its user(s)?
o Functional Requirements Specification: How each feature of the system functions?
o Design Requirements Specification: How each feature of the system is built?
o Hardware Requirements Specification: Minimum hardware required to support the system.
FDA Definition: “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 attributes.” (Source: FDA Guidelines on General Principles of Process Validation, 1987)
Significance of CSV
Main business reason behind CSV is to deliver as per requirements and to have minimum maintenance cost for a computer system. Documentation is one of the most important requirements of CSV. It is important for Pharma Systems to be CSV compliant to:
 Minimize regulatory actions.
 Maintain positive relationship with regulatory bodies.
 Expediting submissions to FDA / other regulatory and faster approvals by FDA.
 Avoiding product recalls and negative publicity.
Key FAD Regulations applicable for SAP Projects
Following are key FDA Regulations which are closely related with SAP Software development cycle.
CFR : Code of Federal Regulations ,Title 21 mainly deals with Food & Drugs published by US FDA
 21 CFR Part 11 ( Electronic Records, Electronic Signature )*
 21 CFR Part 210 (Current GMP in Manufacturing, processing, packaging)
 21 CFR Part 211(Current GMP for finished pharmaceuticals)
* The 11 th sub part is related with all kinds of electronic records & Signature for software project
Refer website for country specific regulatory bodies mentioned in reference...................Audit trail of changes
 What type of changes ( Creation, Modification, deletion )
 What record was & what it is now
 Who did it ( Unique identities)
 When it was done
Electronic Signature
 Irrevocable legal signature
 2 Elements ( User ID and Password)
 Password not viewable ( even by system administration )
Access Control
 User Profile
 Password
 Password encryption
Main Benefits of 21 CFR Part 11 are
 Increased speed of information exchange
 Cost savings
 Reduced data entry and errors
 Improved process control
 More efficient data transmission to FDA for review and approvals

Green Validation: Practical Strategies For Paperless Software Validation

2010-09-25T07:26:00.001-07:00

INTRODUCTION
Software validation is a fact of life for highly regulated companies that leverage advanced technology solutions to drive mission-critical regulated business processes. Validation and verification is essential to ensure that these systems meet their intended use and include the proper level of security to protect data and prevent unauthorized access and changes. An essential requirement for all validated systems is that they must be maintained in a validated state over time. This means that validation is a “living” process that requires change over time.

For years, life sciences companies have struggled with the documentation burden associated with software validation. Over the past two decades, there has been much discussion about “paperless” validation. However, the idea of paperless validation as well as other paperless processes has largely been an elusive goal that has plagued enterprise technology. During the early days of document management system deployment, a key driver of these systems was the promise of the “paperless” office environment. After millions of dollars spent on enterprise technology, paper lives on!

Life sciences companies today face mounting pressures to deliver systems with enhanced security, traceability and control to ensure sustained compliance. In addition to these concerns, today's life sciences companies must operate within an environmental, social and economic context where environmental sustainability is a key element of overall business operations. More and more, companies are independently seeking ways to become better stewards of natural resources taking into account the needs of future generations. The overall premise of the “green” economy is to reconfigure business processes and infrastructure to deliver better returns on investments, while at the same time reducing greenhouse gas emissions, extracting and using fewer natural resources, creating less waste. Given this imperative, any improvement in operational efficiency, cost and risk are compelling business drivers to replace inefficient, wasteful paper-based processes with secure, electronic ones. In support of green initiatives, I have been promoting the concept of “green validation”. The term “green validation” refers to a new, more responsible approach to software validation that leverages GAMP methodologies and advanced technologies to promote a paperless validation environment. Now, more than ever, is the time to awaken the vision of green validation and move this strategy from vision to reality.

THE PROBLEM WITH PAPER
There is an old adage in the life sciences community which says “… if its not documented, it didn't happen…” This could explain in part the love affair with paper. Paper is convenient. Most people still prefer to read printed documents in spite of all of the technology we have deployed. Paper is necessary to maintain an audit trail of paper records required by current global regulations. (I am often amused when organizations spend millions on content management systems with 21 CFR Part 11 signatures only to print the paper documents out and sign them by hand.) Yet, what many people don't realize is that paper is EXPENSIVE. Consider the fact that recent studies have repeatedly shown that in most corporate environments, knowledge workers spend up to 40 percent of their time trying to find paper documents. An excessive amount of time is spent searching for and retrieving documents costing billions of dollars of wasted time each year in the US alone. If you consider the fact that according to a recent study, the cost of paper is about .003 cents per sheet. Thus, if a typical life sciences company purchases 10 million sheets of paper annually, the total cost is approximately $30,000. 95% of this paper will have to be disposed of and most will end up in filing cabinets. When you add up the cost of photocopying, printing, faxing, mailing, storage, and disposal costs associated with paper, studies reveal that the costs can skyrocket to nearly $500,000 per year just to manage paper.

As you are aware, validation is very paper-intensive. All initial validation documents and their subsequent changes must be tracked and managed in a controlled manner. In addition, software validation documentation must be comprehensive to support the “intended use” principle. Given the broad range of systems on the market today, one of the main challenges associated with validation is applying a consistent methodology across multiple systems. For commercially-off-the-shelf (COTS) software, this is particularly important. Most COTS vendors offer “validation test scripts” with their solutions. Given the varying levels of understanding of validation among the COTS players, companies must deal with the inconsistencies of the COTS-developed test scripts.

Consider the statement in the guidance for software validation “... computer systems used to create, modify, and maintain electronic records and to manage electronic signatures are also subject to the validation requirements…”

Also, 21 CFR Part §11.10(a) “…Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records…”

Beyond compliance, validation can offer significant business value and can be consider as somewhat of a “legal best practice” in providing traceability and accountability within business processes. FDA regulations are very clear in their expectations that organizations must adopt and follow very specific processes and procedures to ensure compliance. It is important to realize that regulations provide guidance and do not advocate the use of any specific technology to meet regulatory requirements. It is also important to understand that the U.S. FDA as well as other global regulations have embraced and even suggest the use of advanced technology to drive regulated business processes. It is a well established fact that many processes including validation are more effective if driven by technology. Paperless systems help to greatly facilitate compliance audits and help to reduce regulatory risk. From a validation perspective, it is time to move to the 21st century to promote “green validation”.

GREEN VALIDATION: PAPERLESS OR “LESS PAPER”?
Validation lends itself nicely to automation. However, when it comes to validation, there is a clear distinction between paperless validation and validation with less paper. Green validation does not necessarily mean “no paper”. Paper is here to stay. It is a reality and a fact of life. However, there are clear business and environmental imperatives for green validation. How is this achieved? The good news is that there are organizations developing validation toolkits and online electronic validation systems that allow you to track and manage requirements and validation protocols online to effectively produce validation document deliverables using an automated approach.

The concept of green validation includes integrated systems with built in validation best practices such as GAMP to drive validation efforts. Through the use of green validation software, you have the ability to apply validation principles and best practices to any validation project in a consistent, electronic manner. At the heart of the conceptual green validation system is a “requirements engine” that provides the ability to define validation user requirements and automate the tracaeability of the validation requirements to the validation test scripts. The automation of validation traceability will go a long way to save time and expense. Green validation software includes electronic workflows, electronic signatures, as well as requirements tracking and test protocol integration to help facilitate validation. Most importantly, green validation systems include integrated risk assessment to ensure that all validation efforts are conducted according to their defined risk.

With respect to validation project management, green validation systems should have the ability to allow validation project managers to track and manage multiple validation projects easily and provide “validation intelligence” or business intelligence dashboard functionality to allow project managers to quickly identify bottlenecks and address them to keep validation projects on time and within budget.

And finally, no green validation system would be complete without the ability to produce, manage, and track validation deliverables in a secure compliant manner. The system would include helpful reminders of key validation due dates and assess the impact of changes to help maintain the validated state.

TAKING VALIDATION TO THE NEXT LEVEL
Some may think why even consider the environment when discussing validation? As we all try to do more with less, it is about working smarter as well as efficient. Validation is a process that cries out for automation. Companies are spending excessively in terms of validating COTS software applications and creating reams of paper in the process. The same goes for custom solutions. In addressing these challenges of inefficiency and expense, it is prudent to also consider the impact on our environment because it is good business. Green validation systems take software validation to the next level. By leveraging advanced technology, companies can use less paper or paperless processes to produce validation documentation deliverables and maintain their systems in a validated state. Validation 2.0 is taking shape. The technology is here, and the time for green validation is NOW.

Drug target validation: Hitting the target

2010-09-25T07:21:00.000-07:00

Caitlin Smith¹

The route to new therapeutics often ends in costly failure. The secret of success is the rapid and accurate identification of drug targets with true potential, says Caitlin Smith.

David Szymkowski says drug failures can be due to poor target validation.

For the pharmaceutical industry, the Human Genome Project has proved to be both a blessing and a curse. Where potential drug targets were once hard to come by, the industry is now awash with them. This has left researchers with the unenviable challenge of sifting through the data in search of the elusive proteins that are instrumental in human disease.

Akin to seeking a needle in a haystack, this herculean task has boosted the importance of rapid screening technologies. Of the roughly 35,000 genes in the human genome, only a few have known functions. So the task of identifying and verifying a positive lead is key to effective drug development.

Drugs fail in the clinic for two basic reasons: they either don't work or they prove to be unsafe. "Both of these are often the direct result of sloppy early target validation," says David Szymkowski, director of biotherapeutics at the biopharmaceutical company Xencor in Monrovia, California.

Validation is a crucial step in the drug-discovery process. Most drugs are inhibitors that block the action of a particular target protein. But the only way to be completely certain that a protein is instrumental in a given disease is to test the idea in humans. Obviously such clinical trials cannot be used for initial drug development, which means that a potential target must undergo a validation process — its role in disease must be clearly defined before drugs are sought that act against it, or before it is used to screen large numbers of compounds for drug activity.

Deciding to develop a drug against a particular target is a big commitment in terms of time and money. Once a target enters a pharmaceutical company's pipeline, it can take about 12 years to develop a marketable drug. Each new drug that reaches the market represents research and development costs of close to US$1 billion.

"Reducing failures early in development is far more important than filling a pipeline with poorly chosen late-stage products likely to fail, and fail expensively," says Szymkowski.

Model interactions

Purifying proteins for functional assessment at Xencor

Computer models are a fast, relatively cheap option for initial screening of both targets and potential drugs. These models usually focus on how the two types of candidate structures interact with each other.

De Novo Pharmaceuticals in Cambridge, UK, has a suite of software for the process, covering virtual screens, docking programs and ligand-based design.

If the structure of the target protein's active site is known, the company's SiteExplorer can predict potential drug-binding sites, and can evaluate interactions between these sites and the drug candidates. If the structure is unknown, then its Quasi2 software will produce a virtual protein based on molecular features known to be important in binding in other targets. Drugs can then be designed against the model.

De Novo also offers software to aid the design of chemical probes used in target validation. The SkelGen suite of programs can then use these data to generate new chemical structures optimized for interaction with a target's active site.

The company is collaborating with GeneFormatics of San Diego, California, in a programme focused on inhibitors of the M10 family of matrix metalloproteinases, enzymes that are involved in cancer and inflammatory disorders. GeneFormatics is using proteomics to identify the target enzymes and characterize their active sites, while De Novo is running docking models and virtual screens of small molecules against the proteins.

Software that can model drug–receptor interactions is available from a number of companies including Tripos of St Louis, Missouri; Accelrys in San Diego, California; and Metaphorics in Mission Viejo, California. In addition, some software is available free to researchers at non-profit organizations, such as AutoDock 3 made by the Scripps Research Institute in La Jolla, California, and GOLD from the Cambridge Crystallographic Data Centre, UK. Molsoft in La Jolla, California, which makes the ICM molecular modelling software, last month released an ICM browser for the Apple Macintosh.

The Accelrys suite of structural homology programs identifies the possible function, fold family and three-dimensional structure of target proteins by comparing them with sequences and structural homologues of known function. Once the protein's structure is determined, functional information can be gleaned using different modules within Accelrys's Insight II program, which supports a number of processes including X-ray crystallography, nuclear-magnetic-resonance studies and protein engineering.

Target Engine from LION Bioscience in Heidelberg, Germany, aids target selection by offering the ability to analyse gene sequence and expression data, find homologous structures, map potential functional features onto protein structure, view related gene annotation and protein pathway information and use text mining to find functional relationships.

In biotherapeutics, proteins themselves are developed as active drugs. One software suite designed to help optimize protein function is Protein Design Automation (PDA) produced by Xencor. "We don't screen DNA sequences," says Szymkowski. "More specifically, PDA computationally screens massive numbers of amino-acid changes in a known protein structure." It then derives functional information from the three-dimensional protein structure and designs novel features into the protein to optimize its function.

Sense reversal

Xerion's XCALIBUR switches off target proteins by laser.

Another route to target validation hinges on disrupting gene expression to reduce the amount of the corresponding protein, and so identify the physiological role of the target. Examples of this technique include gene knockouts, antisense technology and RNA interference (RNAi).

In the realm of drug discovery, antisense technology — the use of short oligonucleotides to target specific messenger RNAs for destruction — was developed as a way of finding oligonucleotide-based drugs that interfere with gene expression, rather than with protein function. But the technology is currently enjoying greater success as a high-throughput method of target validation because it offers a highly specific and efficient way to inhibit the expression of potential target proteins in vitro and in vivo.

GeneTrove, the genomics division of Isis Pharmaceuticals in Carlsbad, California, is one of the companies active in this field. It is focusing on the untapped pool of potential therapeutic target RNAs for both target validation and drug discovery, says Nicholas Dean, GeneTrove's vice-president of functional genomics. It offers custom target-validation packages that include optimized antisense inhibitors against any target of interest and control oligonucleotides for testing in cell-culture model systems. It also applies antisense technology to target validation in vivo in animal models.

Biognostik, a biotechnology company in Göttingen, Germany, offers a drug-target validation kit that can be used in vitro or in vivo. It includes five target-specific phosphorothioate antisense inhibitors and two random-sequence oligonucleotides to control for nonspecific effects. It has also developed a sequence-design system called RADAR, which determines antisense oligonucleotides based on specificity, minimal nonspecific effects or protein binding, and the ability to be taken up into cells.

Sequitur, a functional-genomics company in Natick, Massachusetts, has a slightly different approach to rapid target validation. It combines an antisense library with high-throughput DNA microarray assays to test the effects of the antisense molecules on gene expression. The company's technology was used recently to validate a major therapeutic target for Alzheimer's disease. Sequitur also carries out target validation based on RNAi (see 'The silent treatment', page 343).

Custom phosphorothioate antisense oligonucleotides for research are available from firms such as Sigma-Genosys at the Woodlands, Texas; atugen in Berlin, Germany; and Integrated DNA Technologies in Coralville, Iowa. Gene Tools in Philomath, Oregon, offers morpholino antisense oligonucleotides, and Danish companies Cureon in Copenhagen and Exiqon in Vedbæk offer modified oligonucleotides based on 'locked nucleic acid' technology that can be used for antisense.

The proteomics approach

One disadvantage of doing target validation at the genetic level is that many genes produce several different protein isoforms, which can have subtly different functions (see 'A question of form', page 341). Post-translational modifications can also give protein variations. As a result, a developing approach in target validation is to focus on manipulating the activity of the potential target protein itself. "As the vast majority of drugs target proteins, validating targets is best done by modulating protein activity, not expression levels," Szymkowski says.

Proteomics — the study and manipulation of the protein make-up of a cell — is making it easier to distinguish and target just one specific form of a protein. This allows researchers to avoid unwanted changes in the expression of other proteins — another potential drawback of genetic manipulations.

Stefan Henning, director of functional biology at Xerion Pharmaceuticals in Martinsried, Germany, agrees that validation at the proteomics level is a powerful approach. "On a technical level, the development of protein microarrays, multidimensional liquid-based protein separation and technologies that manipulate protein expression and protein–protein interactions will have their impact," he says.

Xencor has developed ProCode, which enables researchers to study the functions of a cell's protein make-up. A ProCode library is a protein-expression library from any cell or tissue of interest, in which every protein (after translation) is tagged with a plasmid, a small circular piece of DNA containing its corresponding complementary DNA (cDNA). The library can be expressed in cultures of the appropriate mammalian cells so that proper protein folding and processing are retained. The expressed proteins can be screened for their interactions with potential drugs, and the cDNA tags allow easy identification of any protein that gives a positive reaction.

Xerion's XCALIbur carries out simultaneous identification and functional validation of potential drug targets. Using target-specific antibodies to identify the proteins and chromophore-assisted laser inactivation (CALI) to 'switch off' target proteins by photochemically modifying their functional sites, XCALIbur can validate specific targets for particular diseases or find new potential targets with disease-associated functions.

XCALIbur is incorporated into the Xstream platform, which takes a disease-based approach to target validation. It searches for hits from a suite of antibodies specifically created against the proteome of a diseased cell. The antibodies bind near to functional sites of proteins and contain dyes that are released by CALI, thereby inactivating the proteins' functional sites. If this inactivation has an effect on the disease, the protein is precipitated by the attached antibody and analysed by mass spectroscopy and database searches.

Validation in vivo

One of the most important tests for a potential drug is an assessment of its role in disease in an animal model. But animal models for certain diseases, such as psychiatric illnesses, are extremely difficult to develop.

"The greatest challenge in target validation is the procurement or development of the correct animal models for the human disease in question," says Bob Gordon, De Novo's vice-president of biology. "For example, there are few, if any, reliable animal models for stroke. So validation is effectively done in phase III trials in the clinic. Progress in this disease area is understandably slow and expensive."

In vivo target validation using gene knockouts, in which genes are deleted or disrupted to halt their expression, is a powerful method of predicting drug action. "Many of the targets for the top-selling drugs of the biopharmaceutical industry have been knocked out," says Arthur Sands, president and chief executive of Lexicon Genetics in the Woodlands, Texas.

This kind of target validation is based on the assumption that knocking out the gene for the potential target has the same effect as administering a highly specific inhibitor of the target protein in vivo.

"With the effective use of mouse knockout technology, expensive drug-discovery activities can be focused on the drug targets that are most likely to lead to breakthrough therapeutics," says Sands. Furthermore, target-specific side effects can be discovered before time and money are invested in drug design.

But mammals are not the only creatures in use — zebrafish have recently entered the fray as a model animal for some human diseases. The fish are more affordable, easier to keep, and faster to raise than mammals, giving a higher-throughput system. Drugs can also be tested for toxicity and their potential therapeutic activity against the target more easily than in mammals.

Perhaps surprisingly, genes that cause disease in zebrafish are similar to those in humans, for example in angiogenesis, inflammation and insulin regulation. The transparency of zebrafish embryos also makes them suitable for large-scale, high-throughput genetic and drug screens.

Zygogen in Atlanta, Georgia, has developed a transgenic zebrafish system called Z-Tag which can be used for target validation. The company can also make various zebrafish organs visible by tagging the tissues with fluorescent markers.

One of the most widely used models of human disease is the mouse, but working with mice can be both time-consuming and expensive. Lexicon Genetics has met this challenge by industrializing the generation of mouse knockouts, using gene targeting, gene trapping and mouse embryonic-stem-cell technologies. The result is the company's Genome 5000 programme, which aims to analyse 5,000 genes over the next five years — over 750 have already been done. Custom transgenic and knockout mice are also available from Deltagen in Redwood City, California, and memorec stoffel in Cologne, Germany.

Researchers are slowly but surely making progress in validating the targets revealed by the Human Genome Project. But proving that a target protein has a causative role in human disease remains a real challenge. "The most exciting technologies are, and will be, those that address the issue of elucidating causative roles of targets in human disease, as opposed to simple associations," says Aram Adourian, a senior director at the biopharmaceutical firm Beyond Genomics in Waltham, Massachusetts (see 'A whole picture', page 345).

More challenging tasks lie in discovering the effects of interactions between newly validated targets in both healthy and diseased models. Such complex information will require not only information systems to correlate multiple variables and outcomes, but also a sophisticated knowledge of protein–protein interactions under a variety of conditions. But for now, researchers are taking it one target at a time.

A Risk-Based Approach to Cleaning Validation of APIs

2010-09-25T07:17:00.001-07:00

Abstract

Arisk-based assessment of cleaning validation of an Active Pharmaceutical Ingredients (API) facility is reviewed. The potential application of visible residue limits (VRL) in cleaning validation
is explained for both pharmaceutical pilot plant and manufacturing facilities. VRLs are the level down to which API residues are visible to a group of trained observers operating under defined viewing conditions.
The author describes the development of a VRL program in an API manufacturing facility including sample and viewing parameters. The effects of observer distance, ambient light intensity, viewing angle and residue appearance were quantitated and the best opportunities for success were defined. Potential applications of VRL implementation were identified in both pilot plant and manufacturing settings.

Introduction

Information regarding cleaning validation in facilities that manufacture active pharmaceutical ingredients (APIs) is limited (1 - 4). The objectives of cleaning validation efforts in the API area are the same as those in the pharmaceutical production area but the areas are fundamentally different. The API facility includes reactors, transfer lines and pipes, pumps, filters, centrifuges and dryers making cleaning validation more challenging. Although up to 90% of the total equipment surfaces are visible, many of the visible equipment surfaces are not within reach of the operator.
The areas that are not visible often represent some of the worst-case locations in the equipment such as low-flow areas or parallel flow routes. These surfaces cannot be visually inspected without the aid of remote access capabilities, such as a remote video system. It must be decided whether to test these areas either with such a remote video system, dismantle the equipment for direct visual examination, or monitor with an indirect test such as rinse sampling. Rinse sampling is by far the most convenient form for monitoring these remote areas on an ongoing basis.
A validated cleaning program based on quantitative visual inspections in conjunction with swab or rinse testing is possible. Acceptable visible residue limits (VRLs) can be established in conjunction with and compared to swab results. Assuming the swab results demonstrated a validated cleaning procedure, if the results are in agreement, then the VRLs may be used going forward. This is the same argument that has been successfully used to defend the use ofrinse sampling established in conjunction with swab results.
The use of only visual examination to determine equipment cleanliness was proposed as far back as 1989 by Mendenhall (5). He found that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The FDA, in their "Guide to Inspection of Validation of Cleaning Processes," limited the potential acceptability of a visually clean criterion to use between lots of the same product (6). LeBlanc also explored the role of visual examination as the sole acceptance criterion for cleaning validation (7). The adequacy of visible residue limits continues to be a topic of discussion.
Visible cleanliness is the absence of any visible residue after cleaning. Although this is a seemingly straightforward definition, a number of factors influence any determination. The most obvious is the observer. Not only the observer's visual acuity, but also training on what to observe, influences the outcome of a visual inspection. The levels of illumination in the inspection areas and shadows caused by the equipment influence what is seen. The distance and the angle of the observer from the equipment surface also have an effect. Finally, the individual residues that comprise a given formulation affect the overall visible residue limit.
Fourman and Mullen determined a visible limit at approximately 100 μg per 2 x 2 in. swab area (8) or about 4μg/cm2. Jenkins and Vanderwielen observed various residues down to 1.0 μg/cm2 with the aid of a light source (9).
For this study, the visible residue limits of active pharmaceutical ingredients were determined.
Observers viewed residues under viewing conditions similar to those encountered in both a pilot plant facility and a commercial manufacturing facility.

Visible Residue Parameters

Pilot Plant Study
Since the determination of a visible residue limit is, to a large extent, subjective, the variables associated with studying visible residue were defined, and then experimental parameters for the study were established. The parameters considered were: residue, surface material, light intensity, distance, angle, and observer subjectivity (10).

Steam Sterilizer Validation Requirements Per The New Standard ISO 17665-1:2006

2010-09-24T06:04:00.000-07:00

For decades, steam sterilization (autoclaving) has been an integral part in the manufacturing, cleanroom, and laboratory processes for the medical device, pharmaceutical, biologics, and human tissue/HCTP industries. It has been a common industry practice to validate steam sterilizers using the published guideline ISO 11134 Sterilization of health care products — Requirements for validation and routine control - Industrial moist heat sterilization,¹ issued in 1994. In late 2006, AAMI released the document intended to supersede 11134, with ANSI/AAMI/ISO 17665-1:2006 Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.² While other steam sterilizer guidance documents do exist,^3,4 it is anticipated that the new 17665 standard will be recognized by the FDA and will be commonly employed to validate autoclave processes. The good news to manufacturers or other users of these guidelines is that many of the current validation practices are the same in the new document. This article will outline the basic requirements for steam sterilizer validation via the halfcycle overkill method, and list some of the differences between the two documents.

REQUIREMENTS PRIOR TO VALIDATION
The 17665 document makes it clear in numerous locations that the user’s quality system must adhere to ISO 13485:2003 Medical devices — Quality management system — Requirements for regulatory purposes.⁵ So if a user wishes to claim full compliance with the new 17665 steam standard, then their quality system must also be in compliance with ISO 13485, including items such as preventive/periodic maintenance and regular calibration for the sterilizer, documentation, change control, purchasing, etc. When compared with the previous steam document, the new 17665 also has more information on product and process characterization, sterilizing agent characterization, installation qualification/IQ, and operational qualification/OQ. The new document also states more clearly that a fully compliant validation is not just a series of successful halfcycles,but is the full complement of successful IQ, OQ, and PQ.
Sterilization agent characterization will be simple for most users — moist heat/steam at 121 or 132 °C, and cycle selection (gravity, prevacuum, etc.). Process and equipment characterization means defining and documenting items like the sterilizer cycle parameters, products (or product families) to be sterilized, load configurations and limits, placement of biological indicators or chemical indicators (BIs/CIs), process tolerances, and equipment identification. Much of this type of information would be recorded in well-written validation protocols or validation final reports. Biological indicators often use spores of the bacterial species Geobacillus stearothermophilus at a titer of greater than 106per BI, although other species or titers are sometimes used.
The new 17665 document also has more information on IQ and OQ. It defines IQ as “obtaining and documenting evidence that equipment has been provided and installed in accordance with its specification.” Autoclave installations commonly document items such as the sterilizer identification numbers, location, line voltage and amperage, water supply piping and pressure limits, steam line requirements, filtration, chamber size, structure and support, piping materials, software certification, manuals, drawings and documentation, and calibrations (temperature, pressure, and timer). The sterilizer must be installed in such a manner to facilitate any necessary maintenance, repair, adjustment, cleaning,and calibration.
OQ is defined as “obtaining and documenting evidence that the installed equipment operates within predetermined limits when used in accordance with its operational procedures.” Autoclave OQs commonly test or verify items such as cycle operation and programming instructions, safety and alarm testing,error reporting, empty chamber temperature profiling and chamber temperature limits/specifications, air removal testing, leak testing, temperature control anomalies, full cycle full-load temperature profiles (if proposed fullcycle exposure time is known), and determination of any hot or cold spots withinthe chamber.
The product definition and process definition sections of the new document list things such as product specifications, product families, packaging, re-sterilizationissues, package moisture, stability and potency of container products, re-usablecontainer systems, process challenge devices/PCDs, sterility assurance level/SAL,BIs and CIs, and bioburden determination if necessary. PCDs are described asproducts or items that provide a known resistance to the sterilization process.They are commercially available or may also be created from the user’sproduct line by inserting spore strips, spore dots, inoculated threads, etc.into items or locations that are determined to be the most-difficult-to-sterilizeproduct or location in the load.
There are many other activities or decisions to be made prior to or during the IQ/OQ, that are not necessarily detailed in either standard. Items such as:

Obtaining calibrated temperature recording devices or thermocouples
Ordering supplies such as BIs, CIs, Bowie-Dick test packs, packaging materials, etc. and noting if adequate laboratory facilities are available
Determining worst-case validation load and worst-case test product or PCD. The protocol or final report should contain a written rationale describing how the loads and product(s) were selected
Selecting cycle type: 121 or 132 °C, gravity or prevacuum cycle, etc.; and determining if drying time needs to be qualified
Is product bioburden testing necessary?
Is product resterilization to be allowed and what are the requirements for resterilization?
Is product stability or shelf life testing necessary for the user’s products?
Does packaging testing or packaging validation need to be included with the protocol?

VALIDATION – PERFORMANCE QUALIFICATION
AAMI TIR #13 states “Sterilization process validation is a documented procedure for obtaining, recording, and interpreting the results required to establish that a process will consistently yield product complying with its predetermined specifications.” For the purposes of this article, the primary specification will be sterility. The performance qualification/PQ or microbiological qualification is a series of tests that establishes that the installed and properly operating sterilizer will process the users desired chamber loads to achieve the specified sterility assurance level/SAL. It must be remembered that the load is part of the validation — that is, if the user makes significant changes to the load at any point in the future — then re-validation may be necessary. The previous ISO 11134 document gave relatively little guidance information and few specifications for conducting the test cycles necessary to qualify the user’s proposed fullcycle exposure time(s). The new 17665 steam document varies little from the previous standard in respect to the minimal PQ information that is provided. The 17665 describes bioburden validation methods and the more commonly used halfcycle “overkill” method. It should be noted that at the time this article was prepared, the proposed guidance document that is to accompany ISO 17665-1 was not yet available. This guidance document may provide more advice on microbiological qualification issues (ISO 17665-2 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1). For this article, the general requirements for an overkill cycle PQ will be reviewed.
While many activities are required to complete the PQ, the primary goal for the commonly employed overkill validation is this: the user needs to complete three consecutive successful halfcycles in order to qualify their proposed fullcycle exposure for routine processing of sterilization loads. In our case, successful means all BIs are killed (no growth upon incubation) for the three consecutive halfcycles. If, for example, there was no BI growth for the three test cycles at ten minutes exposure at 121 °C, then a 20-minute exposure at the same temperature would be adequate for routine daily processing, assuming all other aspects or requirements of the IQ/OQ/PQ are successful, documented, reviewed, and approved.
But a description of the PQ needs much more detail than this. Validation protocols vary in format from company to company, but most will capture similar information for the final report. An example of validation protocol and final report sections would be:

Title page with approval signatures
Purpose, background information, or general goal(s) of validation
Scope with more specifics about methods, cycles, facility, SAL, products and load, exclusions, etc.
References with published standards and company SOPs
Equipment, supplies, validation loads, BIs, etc.
Rationale for selection of products, load, cycles, PCDs, etc.
Procedure or methods (more details on this below)
Acceptance criteria which list the pass/fail requirements
Deviation report which lists any unexpected results, with potential effects on the validation, along with accept/reject rationale
Results and conclusions which assign a pass/fail decision to each acceptance criteria, summarize study, and include any requirements for revalidation
Attachment which lists any data sheets, diagrams, certificates, temperature records, etc., for inclusion with final report
Approvals section for final report.

To conduct the halfcycles, the user assembles the worst-case validation test load, temperature loggers, BIs/PCDs, and CIs if necessary. The temperature loggers and BIs are seeded throughout the load to represent various chamber locations, keeping in mind any cold spots or previously determined most-difficult-to-sterilize locations. For small chambers, as few as five or six BIs and temperature loggers may be needed. Ten is a common sample size for many chambers. Large, multi-pallet-sized chambers may require many more samples per run. The sterilizer is programmed for one-half of the proposed full-cycle exposure time. Upon completion of the test cycle, the BIs are immediately removed and incubated, and the test load must be allowed to return to normal temperature prior to starting another test cycle. Temperature recorder data is downloaded and printed immediately to determine if any unusual temperature conditions existed. Information is entered on thedata sheets (data sheets that would have been one of the attachments to the written protocol), and all temperature records and data sheets are retained for the final report. BIs are checked regularly throughout the incubation period, and include positive control (unprocessed) BIs which must show growth. As stated before, all processed BIs must show no growth in order for the validation runsto be considered successful.
Final reports should contain: 1) all sterilizer run data or recorder charts, signed and reviewed; 2) all temperature recorder data, signed and reviewed; 3)all data sheets with BI, CI, or any other test results, reviewed and signed;4) any deviations recorded and investigated, with final disposition; 5) results,conclusions, and discussion; 6) calibration documents for any measuring instrumentsused during the study; 7) the approved full-cycle parameters and acceptable placementlocations for BIs for normal processing; and 8) manufacturers’ certificatesof analysis for any items such as BIs, growth media, growth promotion test cultures,etc. Including digital photographs of sterilizer, load, PCD, etc. can be quitehelpful for an auditor who may be reviewing the report at a later date. The completedfinal report packet must then be routed for review and signed for approval.
POST-VALIDATION
There are still issues to be addressed when all activities seem to have been completed. The sterilizer must be added to a regular and documented calibration program. The sterilizer must be included in a regular and documented periodic/preventive maintenance program. And the sterilizer must be added to the validation schedule for its annual requalification. The user needs to verify that all personnel that will be using the autoclave are trained using applicable operation and safety SOPs. Untrained staff should not be allowed to run the sterilizer. Approved products, loads, cycles, and load limit information must be readilyavailable to all operators. SOPs for daily processing must list all requirements for data that is to be reviewed and retained from the sterilizer runs, with logbook, filing system, or archive for run records. SOPs must also address items such as 1) segregation of processed and non-processed product, 2) storage requirements for processed products if necessary, 3) notification of management or maintenance if sterilizer malfunctions or if recorder chart lists any errors, cautions, or warnings, 4) immediate notification of management for BI test failure, including investigation and product quarantine procedure as appropriate, and 5) resterilization requirements if resteril-ization isto be allowed.
In summary, there seem to be no drastic or revolutionary changes in making the transition from ISO 11134 to ISO 17665. The new 17665 steam document provides more information and more guidance in some areas, while leaving other areas (such as PQ) relatively unchanged. While users would be advised to obtain the 17665-2 guidance document when it becomes available, it is anticipated that manufacturers will not find any great difficulties in applying the new standard.
References

ISO 11134:1994. Sterilization of health care products — Requirements for validation and routine control — Industrial moist heat sterilization.
ANSI/AAMI/ISO 17665-1:2006. Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.
AAMI TIR No. 13-1997. Principles of Industrial Moist Heat Sterilization.
PDA Technical Report #1. Validation of Steam Sterilization Cycles. Parenteral Drug Association.
ISO 13485:2003. Medical devices — Quality management systems — Requirements for regulatory purposes.

Evaluation of Validation Content Uniformity Test Results Using Lower Probability Bound Distribution Charts

2010-09-24T05:58:00.001-07:00

By Pramote Cholayudth

One of the widely recognized references on process validation with regard to sampling and testing plans is the US Food and Drug Administration’s Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment (1) that is based on the Product Quality Research Institute (PQRI)’s Recommendation Report (2). However, it is a non-binding document (i.e., the industry may use any alternative approaches even after it becomes the official guidance). Another well-known relevant reference is the PDA Technical Report No. 25: Blend Uniformity Analysis: Validation and In-Process Testing (3). The sampling, testing, and corresponding acceptance criteria limits in validation study will follow these two statistics-based documents. The validation test results with respect to critical quality attributes (CQAs) require to be statistically evaluated (e.g., estimating confidence limits as appropriate, demonstrating the high probability of passing the tests, etc.).

According to Torbeck (4), “… If statistical procedures were given in the USP, companies would have little incentive to develop better procedures.” His comment is now reconfirmed. The industry may not have a good approach like J.S. Bergum’s method if the United States Pharmacopeia (USP) provided some kind of statistical procedures. Bergum is one of the leading professionals who suggested the use of the new statistical procedures. His methods (5, 6) introduced both how to establish the validation acceptance criteria and how to evaluate the validation test results. In protocol development, all the validation practitioners may follow some recognized documents including Bergum’s in establishing the acceptance criteria limits. However some of them may not be confident in using statistical tools for evaluation of the test results, especially for the multiple stage tests (e.g., content uniformity and dissolution).

To provide an alternative to such a statistical evaluation, this article introduces an approach to using lower probability bound distribution charts, constructed according to Bergum’s methods, for evaluation of content uniformity test results.

Laboratory Equipment Validation and the Importance of a Manufacturer

2010-09-24T05:57:00.000-07:00

Many types of equipment in both manufacturing and laboratory areas are critical to a properly functioning pharmaceutical process. The validation of laboratory equipment is not as clearly defined as the validation of equipment used directly in the production of pharmaceutical products, which requires thorough validation in almost all situations.Should My Laboratory Equipment Be Validated? The evaluation should begin by determining the requirements of the end user, which are often defined in the User Requirements Specifications (URS). Additionally, it is critical to consider the laboratory applications as well as the associated equipment. Next, a risk analysis should be performed. Some types of equipment may seem less critical, but upon more thorough analysis, their real importance is revealed.
Responsibility for complying with the appropriate industry standards ultimately falls on individual companies, divisions, or departments. Failure to comply with current good manufacturing practices (cGMPs) or good laboratory practices (GLPs) can have serious consequences, including regulatory restrictions — such as the inability to sell the product.

Validation reduces the risks of non-compliance with regulatory agencies. It also can reduce compulsory in-process controls and testing. Validation is a means of improving procedures and final product quality. Rather than adding constraints imposed by regulatory bodies, validation is a process for improving efficiency and quality that ultimately can lead to cost savings. Pharmaceutical companies are responsible for the qualification and validation of their equipment. As a result, they must be able to justify choices concerning these procedures to a regulatory agency auditor. The documented evidence supporting these choices is one of the fundamental requirements of validation. After all, validation is verifying and documenting with a high degree of assurance that specific equipment will perform consistently according to predetermined specifications. The documented evidence presented also must comply with cGMPs, incorporate preventive maintenance, and include a requalification schedule.
It is important that the pharmaceutical company works in conjunction with equipment suppliers to determine the appropriate validation protocols as well as the frequency of requalification. A manufacturer's validation capabilities can be an indicator of the quality of the equipment being supplied.

Water Purification Systems To further discuss validation principles, a single system with downstream effects on manufacturing and testing processes will be examined. The data in a laboratory is impacted by a variety of instruments, including water purification systems. If the water system does not consistently produce purified water, the validity of the data from these instruments can be compromised. Manufacturers' Capabilities When acquiring equipment, particular attention must be paid to the equipment suppliers' ability to provide either direct or indirect help with equipment validation and qualification — even if the qualification will be performed by internal qualification services. When choosing a water purification system that will be validated, it is important to consider more than just the specifications of the water produced. Other equally important factors should be considered, such as the level of service provided and the manufacturers' validation experience. In order to meet user requirement specifications and regulatory guidelines, an equipment manufacturer that has implemented a comprehensive program must be chosen to ensure that their products can be qualified. Evaluation should include consideration of the manufacturer's design, manufacturing process, quality controls, traceability, documented evidence, training for users and service personnel, support for periodic maintenance, qualification, requalification, and other factors (see Table 1).
Water purification systems are essential pieces of equipment in most pharmaceutical laboratories for drug production, drug testing, and quality control applications. The quality of purified water used in these processes ultimately can affect the quality of the final product. This is why organizations such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) frequently state that water purification systems must be validated. As with any other equipment, it is important to work with the water purification system manufacturer to determine the appropriate qualification protocols, how to carry them out, and an appropriate requalification schedule. The manufacturer's knowledge can be crucial, especially if they have developed specific documentation to assist with validation procedures. In addition to meeting cGMP requirements, this documentation also should be applied to each qualification stage and offer users comprehensive help in conducting system qualification.
The engineers who deploy system qualification protocols should be trained in validation procedures and familiar with production processes and regulatory requirements in the pharmaceutical industry. Furthermore, preventive maintenance helps ensure that the water purification system is kept in optimal condition and prevents down-time.
Validation Parameters Since the system qualification begins at the design stage, it is important to have a qualification team involved in the development of all new systems. This enables the manufacturer to incorporate the pharmaceutical requirements for system design and specifications.
An important parameter to be considered for the qualification of water purification systems is the calibration of measuring instrumentation. The product water should be monitored continuously for conductivity and, if required, total organic carbon (TOC) levels using calibrated instrumentation. Water purification systems should be designed specifically to meet USP 28 <643> and <645> suitability test requirements for TOC and conductivity respectively. Also, as recommended by FDA, system alerts should be implemented to warn users if the system is performing outside the pre-determined specifications. Additionally, systems manufactured in an ISO 9001/ISO 14001 certified plant permit good traceability. Certificates of Conformity, Certificates of Quality, and Certificates of Calibration also should be available. The USP specifies that operational qualification protocols be performed on-site after the system has been installed to meet USP validation requirements.
Conclusion Equipment validation is essential. Determining what equipment needs validating starts with ascertaining the requirements of the end user. It then proceeds to a risk analysis with careful attention paid to regulatory requirements. Careful choice of an equipment manufacturer that offers a comprehensive validation services program, incorporating specially-trained personnel, on-site qualification protocols, calibrated measuring instrumentation, and the relevant documentation in accordance with GMP requirements can facilitate the validation process and overall regulatory compliance.
Sean Murphy is worldwide validation product manager for the Lab Water Division of Millipore Corporation, Boîte Postale 307, 78054 St. Quentin en Yvelines Cedex, France, (33)1.3012.7232, sean_murphy@millipore.com

Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility

2010-09-24T05:50:00.000-07:00

Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility

Understanding every aspect of the process should ensure development of a successful cleaning validation program.

Feb 1, 2006
By: José A. Morales Sánchez

José A. Morales Sánchez

Currently, there are multiple publications, as well as guidelines from regulatory agencies that make the critical process of equipment cleaning validation easier. These sources provide in-depth information for the validation specialist, making the development and implementation of a robust cleaning validation program possible within any particular facility developing or manufacturing parenteral, biological, or sterile ophthalmic products. Extremely important, specific, and above all, mandatory, are the requirements established by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration (TGA), etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states:
"Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements."
Additionally, Section 211.182 requires that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established.

This article provides the reader with cleaning validation information enhanced by the author's thirteen years of hands-on experience working in equipment cleaning validation. SCOPE
This article focuses on manual cleaning procedures because these are considered the worst-case scenario. It applies to parenterals, ophthalmic, and biologic presentations and is intended to cover equipment validation for raw materials, contaminants, cleaning agents, as well as the control of potential microbial contaminants associated with those products.

Figure 1. Depiction of Different Aspects for Consideration When Developing a Cleaning Validation Program

The flowchart in Figure 1 graphically shows the different aspects that should be considered when developing a cleaning validation program. Understanding each aspect of the process, the relationships among these actions, and the sequence in which they should take place will make the development of a cleaning validation program a successful experience. PROCESS FLOW
After all applicable cleaning information sources and regulatory guidelines have been consulted, the first item to consider when establishing a cleaning validation program is the raw material and final product flow. By following the flow of the product, one can identify the equipment that comes in contact with it, such as utensils (scoops, spatulas, funnels, pipettes, etc.), tanks, filter housings, pressure vessels, syringes, and others. Equipment such as this is considered critical equipment because it comes in direct contact with the product.
Other areas where raw materials or products are processed, which might be considered non-critical because they are not in direct contact with the product, should also be considered. From the point of view of microbial load, inappropriate cleaning and sanitation of these areas may contribute to cross-contamination. Some examples of these areas include: sampling and weighing rooms, as well as formulation and filling rooms.
Typical steps to follow in process flow are as follows:
Raw Materials Sampling: Raw materials include both active and inactive ingredients. Many active ingredients are potent compounds, such as steroids, cortisone, antibiotics, proteins, and therefore it is important to demonstrate their removal. But be aware that some inactive ingredients have poor solubility in water and their residues may be more difficult to remove than those of an active drug.
Utensils used during the sampling process of raw materials require cleaning validation unless they are disposable. Typically, use of disposable utensils is the preferred practice for parenteral and biological products. The sampling of raw materials should be performed within a controlled environment (classified as 1,000, 10,000, 100,000, etc.,) in order to reduce the introduction of non-intrinsic contamination to the process. Some firms use extraction hoods equipped with high efficiency particulate air (HEPA) filters and room air conditions that provide an acceptable environment for raw materials sampling. In addition, sampling area and rooms should be cleaned with sanitizing agents. Cleaning effectiveness on those surfaces should be challenged using microbiological tests for verification of bioburden reduction of non-sterilized parts, such as tables, walls, ceiling, fillers, etc.
Weighing of Raw Materials: Some rules followed during raw materials sampling also apply to the raw materials weighing process. Some ingredients will require being weighed inside a glove box due to special environmental requirements (e.g., under nitrogen, etc.). Because glove boxes are usually shared, they too will require cleaning validation.
Product Compounding: This is one of the most critical steps because the equipment used will have direct impact on the finished product. Compounding a finished product requires equipment with large product contact surface areas. The handling of ingredients requires utensils with less product contact surface area. This significant difference is important because the more complex the equipment, the more samples must be taken to demonstrate effective cleaning.
Product formulations involve the use of tanks and ancillary equipment, such as gaskets, pipes, hoses, mixers, and filter housings. Gaskets and hoses are disposable in many pharmaceutical processes, so they do not generally require cleaning validation.
Product Filling: Filling of parenteral, ophthalmic, and biologic products is usually performed within areas of controlled bioburden, ranging in scale from clean to aseptic rooms. Drug products are capable of being contaminated in many ways. Contamination may occur via filling components (tips, caps, bottles, or stoppers); when coming in contact with processing equipment (tanks, manifolds, fillers, machine-syringes, pistons, and blocks); the manufacturing environment, or manufacturing operators.
Some equipment may require cleaning revalidation if components come in contact with the product. Stoppers are siliconized and then are placed in a hopper during filling. Small quantities of silicone are accumulated in the lower part of the hopper where it can degrade over time. If this silicone were to come in contact with the product, it would probably cause product contamination.
Requirements for aseptic processing include cleanable floors, walls, ceilings, particulate, temperature, humidity, cleaning, and disinfecting procedures. When disinfectants are used in the manufacturing area, care must be taken to prevent the product from becoming contaminated with chemical disinfectants. The selection of suitable disinfectants, verification of their effectiveness, and a surface challenge are critical in developing a cleaning and sanitization program. Written procedures for cleaning, maintenance, and sanitization of manufacturing equipment and appropriate areas of the facility are required. Removal of residual disinfectants should be monitored as a precaution against the possibility of product contamination.
Know Product Ingredients and Intended Use of the Final Product
Previous to designing the cleaning procedures, it is necessary to know all physical and chemical characteristics of the product ingredients. Characteristics such as appearance, solubility, potency, and toxicity play an important part in the design strategy of a cleaning validation program. These characteristics will indicate whether solvents or detergents are needed for removal of product residues. Avoid the use of detergents or solvents whenever possible because their use demands added controls.
Regarding the intended use of the product, cleaning procedures related to the production of parenterals are the most critical. Great precautions should be taken with the cleaning procedures surrounding these products, because they will be intravenously administrated to patients and any adverse reaction could cause serious damage to patient health.
Developing Standard Operating Procedures (SOPs) for Cleaning Processes
Once we know and understand the product process flow, the product's ingredients, and the product's intended use, standard operating procedures associated with the cleaning process should be established. These procedures should clearly address the specific method chosen, the cleaning process itself, any detergents, and the allotted cleaning time.
There are three types of cleaning procedures for process equipment: automated Clean in Place (CIP), Clean out of Place (COP), and the manual process. However, the major concern of regulatory agencies has targeted pieces of equipment that will be cleaned manually, and where the primary responsibility for the removal of product residues lies with the cleaning operator. In the case of manual cleaning methods, the effectiveness of cleaning depends upon the design of the procedure and the commitment of the operators to follow that procedure. This requires a well-explained SOP, personnel training, and operator commitment. With all three elements present, reproducibility of the results in terms of removal of product residues from equipment surfaces can be achieved.
Cleaning procedures should cover every type of equipment to be cleaned. They should specify all critical parameters including water flow, temperature, and pressure as well as washing and rinsing times. Usually these will have been previously set through engineering studies. Cleaning procedures should also include specific details regarding disassembly of equipment, where the small parts should be placed, the quantity of detergent to be prepared and its concentration, and the type of brush or piece of cloth used to apply the detergent. The size (length, and internal diameter) and the type of hose used to perform the cleaning process should also be specified. This is important because, if the hose diameter is small, less water is used and a higher pressure is achieved during the operation. Finally, cleaning procedures should be challenged and validated to demonstrate the reproducibility of results for all cleaned parts.
Validated Analytical Methods
Appropriate validated analytical methods for analyzing cleaning validation samples will be used. A validated method is rugged and robust enough to measure the residue limit established. The method used should be based upon previously established residue limits of the active, cleaning agents, and excipients. The method must be appropriate for measuring the analyte at and below the acceptance limit for residue.
Two important parameters in an analytical method used for cleaning validation are: the Limit of Detection (LOD) and the Limit of Quantitation (LOQ). The LOD is the lowest amount of a compound that can be detected. The LOQ is the lowest amount of a compound that can be quantified. The LOD is usually lower than the LOQ, but is never higher. The LOD should never be used to establish residue acceptance limits. Residue acceptance limit should be established based on LOQ for accurate measurement.
One of the important considerations in choosing an analytical method is the type of residue to be analyzed. Residues can be active drugs, cleaning agents, or organic compounds. The methodologies available are either specific or nonspecific. A specific methodology detects a unique compound in the presence of potential contaminants. Some examples of specific methods are high performance liquid chromatography (HPLC), ion chromatography, atomic absorption, capillary electrophoresis, and other chromatographic methods. Nonspecific methods detect any compound that produces a certain response. Some examples of nonspecific methods include total organic carbon (TOC), titrations, pH, and conductivity. Currently, methods that are complimentary to each other are applied to cleaning validation samples. That is, if a specific method is used for active and cleaning agents, then a nonspecific method, such as TOC can be used as a complementary methodology. Cleaning validation methodology includes other important parameters such as linearity, ruggedness, method precision, and reproducibility.
A method used to analyze cleaning validation samples is properly designed if it identifies possible interferences. Many possible sources of interferences include active drugs and excipients, cleaning agents and compounds, swab materials, and solvents used in performing the cleaning process. Still other sources of interference may be triggered when a sample is not handled properly.
In addition, the method validation must contain sample stability for the reference analyte. Choice of validation methods should guarantee that samples remain stable for the time specified for analysis. This includes the stability of all residues that specifically determine the active and the detergent residues.
Validated Swab Recovery Study
The swab recovery must be validated to determine the amount of analyte that can be recovered from a surface. Previous to validating the equipment cleaning procedure, the types of equipment surfaces for product manufacturing should be identified. This means if four types of surfaces are identified such as glass, stainless steel, Teflon, or rubber; each of the four surfaces must be tested for swab recovery.
The study can be performed on simulated product contact surfaces. The efficiency of the swabbing procedure should be challenged at the acceptance criteria level for active ingredient, excipients, and detergent.
Known amounts of active ingredient, excipients, and detergent will be added to each type of surface. The surface is air-dried and swabbed. The nature of the swab extraction is dictated by the analytical method, which has taken into consideration its dissolution properties as well as the analytical technique used. The amount recovered by the swab is determined using a validated trace level analytical method.

Recovery from the surface is calculated as follows: A recovery factor of 70% is usually acceptable; but factors as low 50% may be obtained. In cases where low results are obtained in a reproducible manner, the sample surface area may be sampled again using a second swab,with the results obtained from both swabs added together.
Initial Cleaning of New Equipment
Another important aspect to consider when establishing a cleaning validation program is the initial cleaning of new equipment. Most commonly, the equipment included in a cleaning validation study is that which currently is in use for a specific operation. Nevertheless, it could happen that new equipment purchased for any type of improvement or replacement is received and installed at the site while the equipment validation study is being developed. In such case, this is the best time to include the new equipment in the study.
Initial cleaning for new equipment requires some special considerations as noted here. This cleaning should be performed to eliminate foreign matter or residues introduced through maintenance, fabrication, or installation.
Description of this initial cleaning procedure is as follows:

Equipment should be passivated (if stainless steel material) as per current SOP.
Remove passivation residues from equipment surfaces as per existing cleaning SOP.
No detergent will be used during the cleaning process.
Let equipment dry, rub a lint free piece of cloth (preferably white) over equipment surface and inspect the piece of cloth for visible residues.
Take rinse or swab samples to determine the absence of passivation agents by a validated methodology. Additional samples can be taken for pH/conductivity or any organic reagent determination by TOC technique. In some cases, a sample for total plate count determination is also included.
The rinse sample for passivation agents will be collected in a 500 mL glass bottle and the sample for organic test by TOC determination, in a 50 mL glass tube.
The microbiological samples will be collected in sterilized sampling bottles. When swabbing is called for, a sterilized swab should be used.
Take samples as controls from the water source for chemical tests, TOC analysis, and micro-biological analysis, respectively.
Submit the samples to the corresponding laboratories and analyze as per current SOP's.
Acceptable limits:

Passivation agents: ID test according to the chemical used in the passivation process
TOC: Three log reduction of passivation agent's formulation or USP limits
Conductivity: USP limits
Total Plate Counts: The most important consideration in setting any limit here is that it have a scientific basis supported by historical data.

CLEANING VALIDATION PROTOCOL
Once all the aforementioned aspects are considered, we are ready to develop the cleaning protocol. A protocol used to validate the cleaning procedure contains the following basic elements:
A. Purpose: This section describes the intention of the validation protocol.
B. Scope: This lists the boundaries of the project to be validated.
C. Responsibilities: Tasks are listed for each person involved in executing the protocol.
D. Strategy: The following steps should be included in the strategy section:
1. Description of the product to be challenged:

If two or more product presentations are used, the more concentrated should be challenged.
Bracketing may be considered acceptable for similar products and equipment, provided appropriate scientific justification is present.

2. Holding time period for equipment being cleaned:

This is the time during which the equipment was soiled with the product.
Let the residue dry for a specified length of time (hours), followed by cleaning the equipment.

3. Holding time for cleaned equipment:

The rationale to establish this period of time should be based on microbiological challenges in equipment areas identified as inaccessible locations or where the probability of stagnant water can exist.

4. References
5. Cleaning effectiveness measures (rinse or swab)
Measuring and Test Equipment
Check calibrations of instruments used during protocol execution for proper compliance.
Procedure
1. Identify the procedure to be challenged.
2. List all safety precautions established for the affected area.
3. Indicate the number of runs that will be made
4. Describe the equipment to be cleaned, including:

Equipment pictures
Indicate equipment surface area calculations

5. List chemical tests (active, detergent, excipients, pH, and conductivity, as applicable to the method)
6. Indicate the number of samples to be collected, the volume of rinse (mL), the container (e.g., glass) material, etc.
Selection of Acceptance Criteria
Chemical Limits
For any new product, the owner should be consulted for details concerning the therapeutic potential and possible adverse reactions. A determination should be made as to the appropriateness of the limits for that product. If the product is determined to be highly potent or poses the strong possibility of adverse reaction, special limits must be determined. All special limits should be determined on a case-by-case basis.
The lowest therapeutic dose (LTD) of 1/1000 is considered a safe level for residues of active ingredients. The same approach will be adopted to calculate the contamination limit for the cleaning agent, using LD50 instead of LTD. For the products that have excipients, (e.g., preservatives), the acceptable residual level should be set at not more than 1/1000 (three log reduction) of TOC of the product formulation.
The maximum allowable carryover (MACO) limit for the active drug or cleaning agent in mg per swab for a specific piece of equipment or for an equipment process train is as follows:
MACO (mg/swab) =

Where:
LTD = Lowest therapeutics dose (mg) or LD50 for cleaning agent (mg/kg)
D = Highest maximal daily dose (dose units)
W_b = Smallest batch size (g)
W_t = Highest unit dose weight (g)
S_s = Swab area (cm² or in² )
S_e = Equipment product contact surface area (cm² or in² )
R = Recovery factor of active ingredient or cleaning agent
LD50 = Lethal dose of 50% of animal population
Microbiological Limits

Depend on the type of product (e.g., injectable, etc.)
The most important consideration in setting any limit is that there be a scientific and historical basis.

Discrepancies
Collect any unexpected situations that occurred during protocol execution.
Approvals
List approvers will vary with each firm. At the very least, the following should be included: a validation specialist, head management of the affected area, appropriate representatives of the microbiological and chemistry laboratories, and appropriate QA representatives. The protocol must be approved before execution begins.
FINAL REPORT AFTER PROTOCOL EXECUTION
The final report will include the following:
1. Table of Contents
2. Introduction

Include a brief description of the cleaning process that was validated.

3. Data analysis and results

Summarize all validation outcome (use of tables is recommended)

4. Deviation

Any discrepancy found during protocol execution should be satisfactorily explained.

5. Conclusions
6. Approvals

The same personnel who approved the validation protocol should approve the final report. These individuals included a validation specialist, head management of the affected area, appropriate representatives of the microbiological and chemistry laboratories, and the appropriate QA representatives.

MONITORING SYSTEM
The purpose of monitoring is to assure the adequacy of the equipment cleaning process. It is important to verify that the cleaned equipment performs as it was intended and that it remains in a validated state. Monitoring may be achieved through taking representative samples, and evaluation of product non-conformances; by following through on quality alert notifications and complaints and by conscientiously completing "Annual Products Reviews." Any or all of these should be followed by revisions to change controls as needed.
Failures in any of these areas might indicate the need for revalidation. Revalidation is also required when there is a significant change in product formulation, change, or modification to a process or equipment and change of cleaning agents.
COMMON ERRORS AND RECOMMENDATIONS
The section is based on the author's experience during his 13 years of dealing with cleaning validations.
Common Errors
1. Failing to perform a good process flow, beginning with the raw material sampling process and focusing on obviously important stages such as the compounding or filling process.
2. Failing to train operators well, and failure to instill a sense of high commitment:

Most common mistakes, such as not following procedures, not taking samples at the time specified, improper handling of samples, not reporting discrepancies observed during the specific process executed, etc., undermine high quality performance and contribute to poor results. It is highly recommended to have representation from the validation department present throughout all runs.

3. Missing or inaccurate documentation:

In addition, to the common errors noted above in #2, a lack of documentation also causes difficult situations during future audits, because important key information will be missing during investigations. This is often the basis for general misunderstanding of data.

4. Lack of good coordination and communication between the different areas involved in the validation process:

Examples of poor coordination and communication include samples not being taken on time, required materials not being available, disputes within departments, lack of cooperation, and bad working environments based on placing blame rather than on cooperation.

5. Failing to understand the criticality of the sampling process:

It is very important to take the samples at the time(s) established and for the proper durations (stability), taking correct quantities and volumes, attending to the proper handling and storage of samples, using the correct equipment, and other special considerations for samples requiring microbiological testing.

6. Failure to properly train persons in charge of sampling:

This can have a major impact on the accuracy of microbiological sampling.

7. Not having an effective change control program:

Once the validation process is completed, internal procedures impacted by the validation outcomes must be revised accordingly. It is frequently observed that the communication and follow up systems fail at some point and impacted procedures and activities are not modified.

8. Not having an adequate cleaning monitoring system:

It is frequently observed that changes are made to an already validated system, disregarding the impact those changes might have on the validation state of the total system. Constant communication between manufacturing and the validation department is critical.

9. Failure of manufacturing areas to consider the validation department in internal changes and procedure approval:

Due to lack of technical knowledge in the validation area personnel in manufacturing might overlook or be unaware of important aspects that have impact from a validation point of review.

10. Failure of plant personnel primarily focused on the manufacturing operation, to require compliance with the cleaning validation procedures.
José A. Morales Sánchez is a technical services senior scientist at Janssen Ortho LCC a Johnson ' Johnson Company; 787.272.7463;
.
REFERENCES
1. FDA. "Guide to Inspectors of Validation of Cleaning Procedures," 1993.
2. Technical Tip #3020. "Pharmaceutical Product Contact Surface Sampling." Steris Corporation (Calgon Vestal Division), 410-200-3020. 4/97.
3. PDA Pharmaceutical Cleaning Validation Task Force, "Points to Consider for Cleaning Validation," Journal of Pharmaceutical Science and Technology, Technical Report No. 29, Volume 52, Number 6, 1998.
4. Maria J. Capote, "Documentation For Cleaning Validation: A Protocol Template," pgs 261-271, Volume 2-Number 3, Journal of Validation Technology.
5. Gil Bismuth and Shosh Neumann, "Cleaning Validation: A Practical Approach," Interpharm Press, 2000.
6. Health Products and Food Branch Inspectorate, "Good Manufacturing Practices - Cleaning Validation Guidelines," Spring 2000.
7. Destin A. LeBlanc. "Equipment Cleaning Validation: Microbial Control Issues," Journal of Validation Technology, Volume 8, Number 4, August 2002.
8. Herbert J. Kaiser and Maria Minowitz. "Analyzing Cleaning Validation Samples: What Method?" , accessed July 16,2003).
9. Code of Federal Regulations Title 21, Volume 4, Section 211.67, April 2004.

CHECKLIST-VALIDATION OF VENDORS FOR COMPUTER SUPPLY

2010-09-23T11:50:00.001-07:00

1.0 Company Information

1.1 Human and Financial resources.

1.2 Knowledge of GMP requirements

1.3 Organization

a) Structure

b) Responsibilities.

1.4 Customer Support

a) Installation and service.

b) Technical support

c) User training.

2.0 Quality System –General.

2.1 Management’s stated policy and commitments.

2.2 Quality group’s responsibility and authority.

2.3 Written Company quality plan.

2.4 Management Review of quality system.

3.0 Quality System –Software Development.

3.1 Development Plan

a) Functional Requirements.

b) Software design specifications.

c) Programming standards and procedures.

d) Programming tools.

e) Review procedures.

3.2 Test Plan

a) Types of Tests.

b) Test tools and methods.

c) Error correction and re-test.

d) Test review.

e) Acceptance criteria.

f) Test reports.

3.3 Configuration Management.

a) Organization and responsibilities.

b) Identification and traceability.

c) Configuration tools.

d) Change control procedures.

e) Version identification control policy.

f) Release approval procedures.

g) Configuration history and status report.

3.4 Program Documentation

a) Source code.

b) Logic diagrams.

c) List of all inputs and outputs.

d) List of all modifiable parameters.

e) List of all operator inputs.

f) Description of interfaces to other systems.

g) Description of alarms and interlocks.

h) Description of error detection and recovery.

i) Description of all data displays.

j) Description of all reports.

3.5 Document Control

a) Documents to be controlled.

b) Approval of issue procedures.

c) Change control procedures.

d) Retention and security procedures.

3.6 Personnel Qualification

a) Formal education.

b) Internal training.

c) Experience in software development.

d) Experience with specific programs used.

e) Experience with application.

4.0 Product Information

4.1 Validation Features.

a) Security.

b) Self documentation.

c) Automatic program change audit trail.

d) Simulation capability.

e) Program compare.

f) Revision documentation detail.

4.2 History of Use

a) Customers of all version.

b) Customers of present version.

c) Configuration history and status report.

4.3 Expected File

a) Present version

b) Revised products.

4.4 Revision Policy

a) Notification of problems.

b) Change required to fix problems.

c) Change to add or modify features.

d) Notification of revisions.

e) Support old versions.