Tuesday, December 14, 2010

Why Validation is Important

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


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

Critical Parameters Affecting Process Validation

Validation is an integral part of quality assurance; it involves systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control. Adequate validation is beneficial to the manufacturer in many ways – It deepens the understanding of processes; decreases the risk of preventing problems, defect costs, regulatory non compliances and thus assures the smooth running of the process.
Process Validation is key to a robust manufacturing process
Process validation involves a series of activities taking place over the lifecycle of product and process. Validation requires a meticulous preparation and careful planning of the various steps in the process. All work involved should be carried out in a structured way according to formally authorized standardized working procedures.

What are the Critical Parameters affecting Process Validation?

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

Stage One: Process Design

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

Stage Two: Process Qualification

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

Stage Three: Continued Process Verification

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


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.


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

Good Documentation Practices (GDP) are Critical to Success!

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

GDP requires a consistent approach

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

How can we improve?

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

Have clear training requirements

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

GDP is here to stay

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

When is GDP applicable?

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

GDP all the way!

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

Cleaning Validation Methods

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 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


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 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 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)

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

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
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).


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.


  • 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

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

Monday, December 13, 2010

Concept of Process Validation For Pharmaceutical Industry

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
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.
- 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