An Overview of Pharmaceutical Process Validation of Solid Dosage Form

An Overview of Pharmaceutical Process Validation of Solid Dosage Form.
*Umed A. Nikam, Abhijit V. Jadhav, V. R. Salunkhe, C. S. Magdum
Rajarambapu College of Pharmacy, Kasegaon Tal:-Walva, Dist:-Sangli, M.S. India


Abstract
The present article gives an introduction and general overview on process validation
of pharmaceutical manufacturing process especially tablet manufacturing process.
The principal objective of dosage form design is to achieve a predictable therapeutic
response to a drug included in a formulation which is capable of large scale
manufacture with reproducible product quality. Solid dosage forms include tablets
and capsules. Quality is always an imperative prerequisite when we consider any
product. Therefore, drugs must be manufactured to the highest quality levels.
Process Validation is one of the important steps in achieving and maintaining the
quality of final product. This article covers Introduction, type of validation
,Prospective validation Retrospective validation Concurrent validation Revalidation
,Elements of Process Validation, Product Lifecycle View ,Phases of Process
Validation , Rationale for selection of critical steps and parameters for process
validation, Documentation ,SOP, Validation Master Plan, Validation Protocol,
General notes process variations, critical factors and sample thief ,sampling plan and
acceptance criteria, the validation report, studies on the process validation by all
these parameter highlight the quality output of finished dosage form.
Key Words

Process validation, Quality management, manufacturing procedure, protocol.



Introduction
The concept of validation was first proposed by two Food and Dru Administration (FDA) officials, Ted  Byers and Bud Loftus, in the mid  1970 s in order to improve the  quality of pharmaceuticals Assurance of product quality is derived from careful attention to number of factors including selection of quality parts and materials, adequate product and process design, control of the process, and in process and end product testing1. Due to the complexity today s medical products, routine end product testing alone often is not sufficient to assure product quality for several reasons. Some end-products tests have limited sensitivity E.g.:- In some cases, where end product testing does not several all variations that may occur in the product, which may have an impact on safety and effectiveness, destructive testing is required to show that the manufacturing process is adequate.
Even the details of the equipments and their maintenance were also involved.
Validation Master Plan
An approved written plan of objectives and actions stating how and when a company will achieve
compliance with the GMP requirements regarding validation. VMP is a summary intention document stating the scope of the validation and outlining the methods to be used to establish the performance adequacy. The validation master plan should provide an overview of the entire validation
operation, its organizational structure,\ its content and planning. The main elements of its being the list/inventory of the items to, relevant to product and process controls within a firm should be included in the validation master plan. It even holds the calibration and qualification of equipments, summary and conditions of Validation Protocol.
Validation Protocol
A written plan of actions stating how process validation will be conducted, it will specify who will conduct the various tasks and define testing parameters, sampling plans, testing methods and specifications, will specify product characteristics, and equipment to be used. It must be specify the minimum number of batches to be used for validation studies, it must specify the acceptance
criteria and who will sign \ approve \ disapprove the conclusions derived from such a scientific study. The validation protocol should contain the following elements,

• Short description of the process.
• . Summary of critical processing steps to be investigated.
• . In process, finished product specification for release.
• . Sampling plans.
• . Departmental responsibility.
• . Proposed timetable.
• . Approval of protocol.

Responsible authorities for validation8 ,10
The validation working party is convened to define, investigate, progress, collate, co-ordinate and
ultimately approve the entire effort, including all of the documentation generated. The working part would usually involve the following staff members
 Production manager,
Head of Quality Control (Manager),
Executive-QC, Head of Engineering
(Manager), Production executive,
Validation Executive, Validation
Manager, Head of Quality Assurance (Manager).

Selection of Critical Steps and Parameters for Process Validation

Granulation
It is the process of collecting particles by creating bonds between them. It is most critical step in tablet manufacturing as virtually all tablet characteristics like flow, weight variation, hardness, disintegration, and dissolution etc. depend on the granulation parameters. The granulation variables that need be controlled are;

• . Mixing speed
• . Granulation time
• . Feed rate
• . Amount of binder solution and its concentration

By controlling the above parameters, one can control the granule strength (fines) and density of granules, there by having a more smooth compression process. Another important aspects is
the granulator used, because high shear-granulators like RMG, Iodize
mixer produces denser granules compared to low shear granulators like FBG, their by questioning their suitability for fast-release preparation.
Drying
This step involves drying of wet mass. Moisture content in granules is an important factor, which has bearing on tablet characteristics. Hence to control moisture content, critical process variables like inlet temperature, drying time are to be monitored and controlled, if the moisture content is less (over dried granules). It produces fines upon milling, which in turn causes weight variation, capping and
chipping. Drying time needs to be controlled, because shorter drying period results in granules having
entrapped moisture, which during compression escapes from the granules having entrapped moisture,
which during compression escapes from the granules and causes the granules to stick to punches (case hardening) where as longer drying period produces friable granules.
Blending
It involves mixing of granules with other blending materials. The purpose of blending is to get uniform distribution of drug, appoint that becomes critical for low dose products like tablet and to impart good flow and anti adhesion property to the blend. Here the critical controlling variable is the mixing time, as under blending will result in segregation of blend and increase in disintegration
time due to coating of the granules with low melting lubricants like stearates. Hence content uniformity testing of drug is to be done at periodic intervals.
Compression
The major variables affecting the compression process are machine speed and compression force.
Variation in the machine speed leads to varied die fill volume hence varied tablet weight. Compression force needs to be controlled as it affects the tablet hardness, thickness, and
disintegration time and dissolution rate. Another controlling aspect is the machine vibration as excess vibration lead to segregation of blend in the hopper and altering the uniform distribution of the drug in the tablets.
Blister packing
This process involves packing in polyethylene lined aluminum foil and PVC blister pack. Temperature of rollers (sealing and forming) and speed of machine are critical
variables. Adequate forming roller temperature is essential to get proper blister formation. Adequate sealing roller temperature is essential to get proper sealing. Less temperature will leaf to leakage and higher temperature will result in burning or spoilage of aluminum foil and PVC. Leak test and
physical evaluation are carried out to establish the above variables during
blister packing operation.

In spite of the method we select for tableting we have some parameters which are to be considered during the process. These parameters were measured or estimated for process validation of the method. The parameters are: Process validation is generally done with three consecutive
batches. All the critical parameters were evaluated for fixing the optimum process parameters. Every processing step is validated for all the three batches and the results obtained must be present within the acceptance criteria, such that the product can be forwarded for the commercial production. All the problems that arise during validation are overcome and the product will be kept ready for the commercial batch production.
Sample Thief
A significant improvement in sampling can be achieved with the use of sample thief, sometimes
known as a grain thief of historical reasons. This device consists of 2 tubes one fitting tightly inside the other and with along holes cut through the tubes in corresponding positions. One end of the outer tube fitted to a point to facilitate is insertion in to a bulk powder the sampling procedure consists of rotating the inner tube to close the holes, inserting the device into the powder, rotating the inner tube
to open the holes, allowing the powder to enter the device, rotating the inner tube once more to close the wholes and finally removing the thief from the bulk powder wholes and finally removing the thief from the bulk powder The thief sampling is better method than merely scoping off it is still an inferior technique the top of a bulk powder Even through most thieves have relatively sharp ends; the very act of plunging the thief through the bulk powder must perturb the sample to some degree.
A compression force of the thief as propagates ahead it is pressed into the bulk thus potentially of the bulk changing the strata and alteringthe wall of powder at the outer walls of the thief. Furthermore, because large particles will flow more easily than will small particles, an opened thief is liable to be filled preferentially with the coarse fraction of the particle distribution
Working procedure by sample Thief
The sleeve rotates so that the interior compartment is isolated from the bulk powder, while in the
closed position, the thief is plunged into the central mass of the powder. Once the thief is at the desired position, the unit is rotated so that the interior compartment is now exposed to bulk powder. Powder flows into the thief compartment of its own accord. Once the interior compartment of the thief is filled, the sleeve of the thief is rotated so that the interior compartment is again isolated from the bulk powder. The thief is then withdrawn from the powder, and the sample is analyzed.
Sampling Plan and Acceptance Criteria
It is the responsibility of the manufacturer to ensure that the sampling plan and acceptance criteria
defined are adequate to ascertain that the manufacturing process is well- controlled and robust to produce drug product consistently meeting specifications. The following sampling plan and acceptance criteria provide a guide for the process validation of a typical solid oral dosage manufacturing process with medium risk indication. Other sampling plans may be acceptable if
they are statistically sound and justified. The extent of sampling, tests and acceptance must take into
consideration, the level of risk, e.g. the equipment type and capacity, to patient health of the drug product and should be considered on a case-by- case basis. The finished product specifications have to be adequately justified and the analytical methods have to be validated as per the
ASEAN Guidelines for Validation of Analytical Procedures.

The validation report
A written report should be available after completion of the validation. If found acceptable, it should be approved and authorized (signed and dated) the report should include at least the following,
1. Title and objective of study
2.Reference to protocol
3. Details of material
4. Equipment
5. Programs and cycles used 6.Details of procedures and test methods
6. Result (compared with acceptance criteria), and 8.Recommendations on the limit and criteria to be applied on future basis.
Conclusion
Process validation is an integral part of among all validation like equipment validation, cleaning
validation, vender validation etc. Validation is art step of assure to identity, strength, purity, safty, and
efficacy of pharmaceutical product. Applicable and critical parameter for validation process of solid dosage form must be consider to fulfills the requirement of quality assurance of final product.
References
1. Rockville M D. Guideline on General Principles of Process Validation. U.S. Food and Drug Administration., U.S. FDA: 2010.
2. Rockville M D. Guideline on General Principles of Process Validation. U.S. Food and Drug Administration., U.S. FDA: 1987.
3. www.processvalidation.com
4. Chaitanya Kumar G, Rout RP, Ram take S, Bhattachaiya S. Process Validation. The Indian pharmacist, 2005, 14-19.
5. Lambert J. Validation Guidelines for Pharmaceutical Dosage Forms. Health Canada/
Health Products and Food Branch Inspectorate, 2004, 7-15.
6. Satyabrata jena, Arjun G, Anil kumar ravipati N V, Satish kumar D,Vinod K R, David

Validation Deviations

Validation deviations are just a part of life when you are working through validation protocols and test scripts; it’s highly unlikely that you will ever complete a full validation project without raising the odd validation deviation here and there.

So what is a Deviation or Exception?

It’s quite simple it’s an error or a failure which occurs during Verification of Validation.
Types of Deviations

There are three main types of deviations that can occur during a validation project they are:

    Critical
    Non-critical
    Simple

Simple Deviations

Simple deviations are usually classified as documentation or protocol errors, these errors are usually found prior to execution or are “obvious” errors or typos. These deviations have no impact on the validation and offer to real risk to the validation process.

Examples of simple deviations include:

    Wrong test selected for product
    Incorrect specification for product
    Loss of power to the equipment being tested

Non Critical Deviations

Non-critical deviations are errors in the protocol or execution of the validation which have no impact on the validation, there errors are normally found during or after the execution. It is good practice to carry out an assessment to determine if the deviation has any impact. There is no real need to document the risk or lack thereof.

Examples of non-critical exceptions include:

    Operator not trained to perform the operation
    An interruption in the computer system or the equipment’s performance

Critical Deviations

Critical deviations are errors which have an impact on the validation, these errors are found during or after execution. It is good practice in this scenario to carry out an assessment to determine the impact if any.

Examples of critical exceptions include:

    Acceptance criterion failure
    An interruption in the computer system or the equipment’s performance

Deviation Process Flow

SME involvement throughout the deviation process is critical. You cannot document enough, even if all of it does not make it into the final event write up. A CAPA may not be needed for simple events, but consider a CAPA if there are many of them or the same ones repeatedly.

General Process Considerations

It is advisable to commence with the resolution process as soon as the event is observed. Involve the SME’s/QA throughout the process as appropriate and get agreement on next steps and/or results prior to execution, or after the completion. Immediately notify the relevant SME/QA if there is any potential Product/Material impact. Conduct a risk assessment to determine the impact and actions to be taken.
Types of Deviations

Typographical errors
These errors are found prior to execution or are “obvious” errors or typos.

External Issues
Failures caused by factors external to the process or system under test.

Execution Errors
Failures to follow instructions within the Test Document or referenced procedures.

Document Generation Errors
Incorrect detail in procedures, acceptance criteria or referenced documentation.

Acceptance Criteria Failures
Pre-defined acceptance criteria have not been achieved.

Things To Consider When It Comes To Qualifying Autoclaves

Autoclave Validation / Qualification is mandatory for all machines used for biological sterilization, in the biomedical and pharmaceutical industries. Sterilization can be accomplished by either physical or chemical means. The principal physical means is autoclaving; other physical methods include boiling and dry heat.

Chemicals used for sterilization include the gases ethylene oxide and formaldehyde, and liquids such asglutaraldehyde . Of all these sterilants, autoclaving is the fastest and most reliable, which is why the regulators always scrutinize autoclave validation / Qualification activities.

Here are 10 items to consider when qualifying autoclaves.
1. Testing of Steam for Porous Product Sterilization

Before commencing temperature testing the correct conditions must be satisfied. The first condition for sterilization of porous product is saturated steam quality. The ideal for steam sterilization is dry saturated steam and entrained water (dryness fraction ≥ 97%). The largest heat transfer occurs when the steam is at boundary conditions. If the steam is dry or contains gas then it cannot condense and its effectiveness is reduced.
2. Equipment Used for Testing

The equipment used must support 21 CFR Part 11 and must be of adequate accuracy. Testing with equipment that is not appropriate can be a major problem so also buy from a trusted vendor. As a small temperature range is required for accuracy (A few degrees) the accuracy of the equipment is very important for the overall measuring chain.
3. System Description of Autoclave

The first impression is very important when the qualification of critical equipment such as an autoclave is at stake. A good description of the system in a protocol shows that you understand how the process works and which critical points you need to keep under control. This description must contain the programs that are used, how they work, how many, where the control probes are located and what regulates this process.
4. Operating Instructions, Calibration and Maintenance

Before the temperature is tested it must be checked whether the operating instruction are valid, whether the instruments are calibrated and what was changed in the system since the last qualification occurred.

Operating Instructions must include parameters of sterilization, the scheme item and position of the control probes in the chamber. The emphasis is on the calibration of instruments because small errors in temperature can affect the Fo value to a great extent.
5. Procedure

One of the most common mistakes is inaccurate testing procedures. The test procedure must be unambiguous and accurate and must not leave the possibility for different interpretations.

Ambiguous: Put the thermocouple in a glass bottle.

Unambiguous: Put the thermocouple in a glass bottle at the contact between the bottom of the bottle and the side of the bottle (This is the most critical place to collect condensate).
6. Load

The most common objections are about loads. That they are not sufficiently described and that regular production does not reflect the qualified load being used.

This can be avoided by item photographing and releasing the same patterns in the protocol and work instructions. This will avoid the arbitrary interpretation of descriptive configuration.

Although sometimes this may seem trite the differences in the temperature profiles of the solution and air filters can be great. Pay special attention to the worst case loads and explain the rationale (mostly filter and silicone hose).
7. The Position of the Thermocouples

The position of the thermocouples must be unambiguous and precise to avoid different interpretations by individuals that perform tests or inspections. You do not want to enter into a debate about where the thermocouple is positioned.

Of course, the critical areas must be covered, and this must be explained in the rationale. When sterilizing liquid loads studies must be done to define coldest and warmest point for min and max load.
8. Acceptance Criteria in the Heat Penetration Tests

Since there are differences in the standards (e.g. PDA Technical Report and EN 285) it would be best if all eligibility criteria are taken into account. Special emphasis should be on equilibration time and temperature because it is a requirement for a good Fo.
9. Deviations

Deviations cannot be forgotten as they may be encountered regularly throughout the qualification process. A robust deviation management process should exist as they may impact the quality of the product. Good handling of deviations help us to improve our qualification, though they are often viewed negatively and not as a mechanism for process improvement.
10. Reports

The report should be accurate as it eliminates the use of data from the protocol and the ability to find errors in them. The report should contain the time and the date of tests, parameters, results related to temperature, BI results , positions of thermocouples, Fo and comparison of results from initial and previous qualification in order to see in which direction the process is moving.
Zeljko Joksimovic
Senior Expert Associate for Validation

Tips On How To Investigate Laboratory & Manfacturing Sterility Failures

Sterility can be defined as the freedom from the presence of viable microorganisms. However, the conditions that guarantee absolute sterility are usually too harsh for active ingredients, and the definition of sterility for a medicinal product must be defined in functional terms.

What do you do when you encounter a sterility failure?

It depends on your perspective!

If you are a Lab Technician you get worried and cry……….if you are a Lab Manager you get furious and try to find out who messed up………if you are QA you reject the batch…………….and if you are part of the manufacturing unit you reject the batch.
How can you settle all these concerns methodically?

The problem can be solved by conducting root cause of the failure.

Investigate:

    What went wrong?
    Where did it go wrong?
    What went wrong?
    How did it go wrong?
    How can it go wrong?
    What & who all are involved?

Investigate the Procedure
The investigation shall be done by a team of professional experts based on company specific written procedures and SOP’s.

Conduct based on Risk
Sterility Failure investigation shall be conducted on a System based Approach.
Laboratory System Investigations

Culture Media

    Media Preparation Details (in-house / ready to use / dehydrated media)
    Negative controls results (passes / fails)
    Growth promotion test results (passes / fails)

Sterilizer & Sterilization

    Media sterilization details
    Sterilizer filter Integrity testing records
    Sterilizer Qualification Reports – any cold spots?

Test Procedure

    Test Procedure / SOP
    Sterilizer filter Integrity testing records
    Analytical manipulations done during testing : Reconstitution / Mixing of the Product

Test Equipment

    Open Sterility Equipments -Requires independent Sterilization and assembly
    Closed Sterility Equipments- Ready to use containers

Test Samples

    Sample Transportation and Handling Procedures
    Records of Sanitization / Decontamination of the sample surface

Analyst

    Qualified
    Training Records
    Self Assessment During Stress Conditions
Environmental Monitoring

    Trend Analysis: Recent Out of Trend data
    Comparison of the recovered organism with that of data bank
    Identification of the organism to species level
    Any typical or atypical organism observed
Cleaning & Disinfection

    Records of preparation of the solution
    Filter integrity testing records
    Reports of disinfection agent effectiveness on the recovered organism



Test Environment

    Sterility Performed in a Uni-Directional Air Flow unit in a classified cleanroom
    Investigate reports for : Preventive maintenence , Air velocity, differential pressure, leak rates , sanitization cycles, cleaning records
    Sterility Performed in an Isolator

Top Tips for Pharmaceutical Automation and Validation

Automation is generally considered as a risky subject because of the specialized and technical nature of work. If there is no understanding of how automation is made and designed, it will be very uncompromising to develop an automation system validation strategy. Several studies of software projects have recorded success rates of less than thirty percent, where it was measured based on the schedule, meeting cost estimates, and satisfying requirements.

There are many ways to do automation projects poorly, but just a few ways to do them correctly. The availability of enhanced software tools and techniques makes it visible and testable for the application to the mainstream of the project. This article focuses on new practices and tools to reduce the complexity of the process.
Structure of Automation Projects

Pharmaceutical automation is tough, but when successful, it is very rewarding.

This is the formula for success:

    Meeting schedule milestone and cost estimates;
    Sustaining automation requirements and quality standards;
    Make automation system work right away;
    Satisfying the owners of the business or facilities.

Since, the automated systems will be integrated to the production equipment; this can greatly affect operations, maintenance, profitability, and safety of the finished production facility.

The pharmaceutical industry is regulated by the U.S. Food and Drug Administration (FDA) and the international Ministry of Health. These regulations apply to the manufacturing of drugs and medical devices including the use of computers to manufacture these products.

Since then, the industry’s automation professionals have developed the business processes to support a cradle to grave, life-cycle approach to automation. The industry has had a lot of opportunity over the years to apply business processes to support the delivery of automation.
Beating the Odds

Improve your chances of success with planning, requirements, testing, and documentation. In pharmaceutical automation projects, define and fix your requirements. Have a robust plan, attain management support, and keep the discipline to execute the plan.

There should be organization, consistency, and coordination all throughout the project. Tasks and requirements should be well-defined in the different phases such as design/review, procurement/delivery, and commissioning. Documents are software’s deliverables and these should be specified and given proper resources.

Existing organizations involve in the project such as QA, engineering, maintenance, validation, regulatory affairs and production committees, should be made aware of the scope of their functions and responsibilities. In the later part of the article, we will discuss in detail some techniques and pointers to have a smooth implementation flow.
Conditions Encountered In Project Management

Design specifications should be detailed and complete. Project managers should work hard to complete all information needed. A structured approach that begins with a plan can increase your odds of success. An automation validation master plan defines at a high level the expectations for quality, requirements, testing, documentation, review, and approval. It would also cover expectations for security, change control, maintenance strategy, contingency planning, and periodic reviews.

Since manufacturing facilities are very complicated, design policies should be clearly established recognizing the interest of various stakeholders to attain balance for an efficient operation. The other main part of the plan is to get it approved by the business leaders. In the preliminary planning of a proposed automation upgrade project, controlling cost was identified as the primary issue with getting approval.

For example, the automation team will probably be asked to significantly reduce the estimated cost for the proposed project.  If you have a robust plan, obtain management support, and maintain the discipline to execute the plan, you can achieve your targets. Define the requirements before you start the design, and get the key stakeholders to agree to them. Communicate broadly and keep the requirements fixed during the course of the project design, implementation, and through start-up.
Control Strategy

Along the way, changes cannot be avoided and they would affect the project design, costs, and schedule. A well-established and effective control process is very important. To maximize control, define and fix your requirement.

Accurately define the automation project requirements with the help of the users of the automation system. They should be measurable and testable identifying the industry, tools, and development needs.
Testing

Tests should show the expected functionality of the equipment. Comprehensive and quantitative tests should be created in accordance with the actual specifications to achieve their purpose. The success of testing depends, in part, on good requirements. If a process automation professional has solid and fixed requirements, it would be a lot easier. Inappropriate testing will increase cost and extend the development time. Testing reduces start-up issues.

If a developer does too little testing during the development process, there will be mistakes in the process control application code. The software will then have to be fixed later in the development process or during start-up of the manufacturing equipment in the facility. The sooner a designer catches a mistake, the cheaper it is to fix. Appropriate testing can reduce overall project cost and reduce rework during start-up.
Author

Mark Richardson
IT Quality Specialist
Premier Infrastructure

Disinfectant Testing and Validation

A controlled manufacturing cleanroom environment requires a sound disinfectant testing program. Disinfectants utilized in routine cleaning must be validated to confirm their effectiveness for use. Proper rotation of the disinfectants can be determined based on the data collected in this study.
Why should I choose Microtest Laboratories to perform my disinfectant validation study?

• Microtest is a high-quality laboratory that has been performing microbiological work for more than 25 years.
• Our specialized microbiology group possesses years of experience performing qualification work on many different surface types using a wide range of disinfectants.
• Microtest has an internal collection of ATCC organisms ready for use onsite, plus the ability to identify and cryopreserve client environmental isolates.

How do I know which method to follow for my disinfectant testing study?
Tube Dilution Method

• For clients with new facilities with little or no environmental trending history.
• Utilizes ATCC strains and some environmental isolates, where applicable.
• Isolates are directly inoculated into the desired concentration of disinfectant being tested.
• Studies of this sort allow a facility to begin production with some assurance that their disinfectants can kill specific microorganisms of concern.
• Initial screening of disinfectants does not validate that they are effective on hard surfaces.

Coupon Testing Using the Swab Recovery Method

• For established facilities with environmental programs and trending.
• Coupons are prepared from the actual surfaces present in the client's clean room environment.
• The disinfectants are sprayed on the surfaces using the method and contact time that are captured in the client's cleaning procedures.
• To ensure implementation of a proper disinfection program, the FDA recommends the use of the facility's environmental isolates. However ATCC organisms may be used as well.

Microtest can create a proposal for your disinfectant validation study with the following information:

• Quantity of surface materials found in your facility
• Quantity of environmental isolates/ATCC strains to be utilized in study
• Quantity of disinfectants to be challenged against in study
• Quantity of time-points to be challenged in the study (time disinfectant sits on a given surface)