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Page 1: Guidelines for Pharma Industry

Guidelines for Pharma Industry

Pharmaceutical validation In pharmaceutical manufacturing industry Validation is very important part of Quality assurance and in Good manufacturing Practice activities or guidelines. FDA gives special emphasis on validation, also it is one of the prime requirement of all regulatory authorities world wide. It is of great importance in Pharmaceutical manufacturing as well as medical devices manufacturing industry.Validation is a process of collection of documentary evidence , it is a process of demonstration that any of the procedure, process, method, or activity is being adapted is capable of producing consistent and satisfactory result in terms of measurements or in terms of product quality.

To demonstrate this it is required that the systems it self and equipment are properly designed and qualified. To demonstrate that a pharmaceutical product manufactured with any process in any pharmaceutical company it is required to validate many procedures, processes, methods activities associated with pharmaceutical manufacturing including machinery , skills and testing procedures , methods.

Pharmaceutical Validation definition: Validation can be defined as process of establishing through documented evidence a high degree of assurancethat a specific process will consistently produce a product that meets its predetermined specifications and quality attributes. A validated manufacturing process is one that has been proven to do what it purports or is represented to do. The proof of validation is obtained through collection and evaluation of data, preferably beginning from the process development phase and continuing through the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, and personnel), but it also includes the control of the entire processes for repeated batches or runs.

Validation In pharmaceutical is classified as follows1.Cleaning ValidationCleaning validation is carried out to ascertain the procedure and method adapted for cleaning of equipments , and aria , is capable of giving desired cleanness , cleanliness of equipment can be ascertained by caring out trace analysis of active ingredient of previous products active ingredient trace analysis . by doing rinse water analysis or swab test, this is quite good method to ascertain the complete removal of earlier products residue so as to avoid cross contamination we have provided a complete example document for cleaning validation here.2.Process ValidationProcess validation is carried out on the manufacturing process or steps , which are adapted for during pharmaceutical manufacturing . The process adapted in pharma manufacturing should yield a consistent results with respect to quality of product. The laid down process is crosschecked for evidence for efficacy , and the results are documented for each step.FDA guidelines define process validation as follows

Process validation: The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. 

For example in manufacturing of tablets a final mixing step is validated by withdrawing samples from all points in mixer at intermittent intervals , and assay of active ingredients is done, results are plotted against respective sample points and time intervals , the ,most efficient time interval at which there are consistent and satisfactory result for desired content at all sampling point is considered to be the best for the process of final mixing step, and this best time interval point is

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again validated by crosschecking ,and documenting on further three batches. It is one of example of process validation , it can extend to other processes adapted in pharma manufacturing.

If there is any problem in the process just by analyzing the validation results one can know the step point or equipment or process which is responsible for any untoward result. 

Types of validations in pharmaceutical: Following are the types in pharmaceutical validationsWhat is prospective validation? Prospective validation is process of gathering of data and documentary evidence about a product and its process before it is sent to market or for distribution, a new product validation or a validation after making a change in the master formula, to determine if the product meet its predetermined standards. The process starts with designing of batch record , raw material specification and in process specifications and limits ,establishing sampling plan, and equipment lists and required environment controls.

Concurrent validationIs a validation process where in current production batches are used to confirm the compliance of processing parameters and standards. Concurrent validation is the set of validation procedures following prospective validation. Concurrent validation is carried out for ensuring the product batches produced in prospective validation meet the required standards and quality so that those can be distributed in market. Concurrent validation is of great use when the test employed is not destructive and can determine the product meet predetermined standards and quality. Concurrent validation is also carried out on product or process which is previously validated process to ascertain that the product or the process meets required standards and is validated.

What is Retrospective Validation?Retrospective Validation is a type of validation where in the product is already and established process such batches of products which are being sent to market are studied to gather documentary evidence about the efficacy of the process or any in process tests and the product it self, such type of validation can be adapted to validate product and the process even if the product and process is not validated earlier. It also makes use of data from old batches to establish the efficacy and compliance of product or process standards. 

3.Analytical Method ValidationHere the method which is adapted to estimate the content, assay, purity or standard of a pharmaceutical product, tested for its efficacy and accuracy , that is it is assessed if the method adapted is capable of giving consistent and correct results without any error , even though there is change in chemicals, instrument or person .

The method adapted should be such that it should be able to detect the content, assay, purity or standard of pharmaceutical product without any error even if there is a change in change in chemicals, instrument or person and this has to be validated by crosschecking separately and documented as evidence for efficacy and efficiency of method adapted.

4.Computer System Validation: The computerized system which are adapted in manufacturing of pharmaceuticals is tested for their worthiness , if the actual readings obtained from system , and those obtained in manually in process are both matching and are accurate and satisfactory so as to rely completely on the computer systems adapted in the process of pharmaceutical manufacturing and quality control , and quality assurance , and stores activity, rules governing computerised system validation , electronic signature and document generated through computerised systems are included in 21 cfr Part 11 of the United states code of federal regulations.

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Validation Phases:The activities relating to validation studies may be classified into three phases:Phase 1: Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability.

Phase 2: Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the "worst case" conditions.

Phase 3: Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOP's have been followed, including Change Control procedures and qualifying systems ,equipments are required to qualify for following Qualifications:

1.Design qualification (DQ)2.Component qualification (CQ)3.Installation qualification (IQ)4.Operational qualification (OQ)5.Process qualification (PQ)

Design Qualification (DQ)- It consists process of gathering documentary evidence of a particular instruments or machine’s fundamental operational and functional specification of an instrument , and its inherent program , or equipment and details about and its detailed design and its qualifications , why this instrument and is supplier chosen.

Installation Qualification (IQ) - It consists process of gathering documentary evidence and process of Demonstration that the process or equipment being installed complies with all of its qualifications of successful installation in a particular aria , so as to comply with intended requirements of process , with respect to its specifications, is it installed correctly, are all necessary accessories and components installed correctly and its documentation required for continued utilization are installed properly. 

Operational Qualification (OQ) - It consists process of gathering  documentary evidence and of Demonstration of all aspects of a equipment , process are functioning properly and accurately so as to yield intended ,measurements, results quality of a pharmaceutical being manufactured.

Performance Qualification (PQ) - It consists process of gathering documentary evidence and process of Demonstration of all aspects of a equipment , process are functioning properly and accurately so as to produce intended ,measurements, results , intended quality of a pharmaceutical manufactured over a period of time. in a consistent manner

Validation Master PlanIt is a document which identifies and provides complete steps, guide or map or guidelines for caring out a particular validation procedure.Where ever there is requirement of any validation , Validation procedure is first assigned a Validation Master Plan.

The Validation ProcessIt is a process of monitoring ,testing,and evaluation of all steps and process involved in a

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pharmaceutical manufacturing

Validation Protocol : All steps in pharmaceutical process are very important steps, and to ensure the process works with required standard pharmaceutical process validation is carried out, the complete details about validation process stages, procedures, and tests, standards, locations, persons responsible and undertaking or doing validation procedures, etc, the detailed road map detailed information of how to do things in a well documented format to carryout the validation procedure is termed as validation protocol, validation protocol also mentions, what should be done, if there is any deviation from the process, what should be done when the validation batches it self are required to be distributed to market and so on.

Computer system Validation:It requires that the software or programs which are utilized by pharmaceutical companies in manufacturing of pharmaceuticals should work without any error, it provides or leads to an accurate measures or activity .Example Dispensing of Raw Material using computerised system. Process control using a computerised system In 21 CFR Part 11 this topic is covered in very detail and you can read it over here Here screen shot prints are gathered to validate and document that the procedure adapted is leads to correct measures or activityComplete details about Computer system Validation:

Validation Life cycle: Whenever any system or equipment is set for its validation to verify that it meets to the required criteria of operation , and quality, a comprehensive validation life cycle is formed to keep the integrity of the systems validity.Revalidation:It is a most important aspect in validation , once a validation for a drug product, machinery, or equipment, or a water purification system, revalidation is mandatory by current good manufacturing practices, here you will find when to do revalidation 

Annual Product Quality   reviews : is an important aspect in assessing validation effectiveness See here

Standard operating procedure SOP for Annual Product Quality Review

You will find complete guide for validation in pharmaceutical industry here VALIDATIONS IN PHARMACEUTICAL INDUSTRYhttp://whoguideline.blogspot.com/2008/09/validation-guidelines-for.html

Following are some of articles which will be useful for you in further understanding of aspects of sterile dosage form manufacturing 

Requirements of documents for validation of sterilisation process

CFR 21 Part 11

http://whoguideline.blogspot.com/2009/11/us-fdas-requirements-of-documentation.html

How to investigate OOS out of specification resultshttp://whoguideline.blogspot.com/2009/09/how-to-investigate-out-of-specification.html

Determination of Phenol coefficient of a disinfectanthttp://whoguideline.blogspot.com/2009/04/determination-of-phenol-coefficient.html

Sterility testing 

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http://whoguideline.blogspot.com/2009/04/sterility-testing-of-pharmaceuticals.html

Clean Room Classification

Time limitations in sterile pharmaceuticals processing http://whoguideline.blogspot.com/2010/02/time-limitations-in-aseptic-process.html

Aspects of validation of manufacturing process in sterile pharmaceuticals http://whoguideline.blogspot.com/2010/02/aspects-of-validation-of-aseptic_26.html

Good manufacturing practice in pharmaceutical industry  pharmaceutical validation

Also see Aspects of Validation of Aseptic Process and Sterilisation , Sterilization of Equipment, Containers, and Closures  

What is pharmaceutical product information manual (Pharmaceutical product dossier) for registration of   pharmaceutical product to foreign countries

Pharmaceutical Process Validation guidelines

Pharma process validation and concurrent release of PPQ batches 

Process validation aspects of Analytical Methodology. Process Validation Stage 3 The Continued Process Verification. 

Process Validation : Process Qualification and Process Performance Qualification (PPQ) 

Process Design and Process Validation Recommendations  

Process validation and its regulatory, statutory requirements. 

Process Validation and Drug Quality Approach to Process Validation. 

General Considerations for Process Validation and Recommendations 

Terms used in pharma validations and their definitions

Process Validation documentation

Quality by design concept for pharmaceutical industry 

Quality by design concept in pharmaceutical industry an explanation 

We are inviting our readers to participate in building knowledge base on this website by sharing actual experience and issues in pharmaceutical validation and pharmaceutical manufacturing and get them published over this website , and join our elite team of authors .you can participate in interactive activity over this website by answering to questions asked by readers of this website.Write us at submitearticles ( @ ) gmail.comPosted by Martin 

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Process Validation – General Considerations

Recommendations and General Considerations .The guidelines published by US FDA in Jan 2011 on current good manufacturing practices (CGMP) and process validationaligns with a product lifecycle activities concept and process validation activities and also with existing US FDA guidelines onvalidation, including the FDA and International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. 

US FDA states in its guidelines on process validation that they encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle. Also see ( process validation in pharma ) 

The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.The term commercial manufacturing process refers to the manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). For the purposes of this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material.

In the following sections, FDA describe general considerations for process validation, the recommended stages of process validation, and specific activities for each stage in the product lifecycle. 

In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. The following practices should ensure uniform collection and assessment of information about the process and enhance the accessibility of such information later in the product lifecycle. FDA says they recommend an integrated team approach to process validation that includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance). Project plans, along with the full support of senior management, are essential elements for success. Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and approved in accordance with the established procedure appropriate for the stage of the lifecycle. The terms attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process, operating, and equipment) are not categorized with respect to criticality in this guidance. With a lifecycle approach to process validation that employs risk based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful. All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output. In other words, a higher degree of control is appropriate for attributes or parameters that pose a higher risk. The fda says it recognizes that terminology usage can vary and expects that each manufacturer will communicate the meaning and intent of its terminology and categorization to the FDA. Many products are single-source or involve complicated manufacturing processes. Homogeneity within a batch and consistency between batches are goals of process

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validation activities. Validation offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health. Also see ( process validation in pharma ) 

Quality by Design Concept

Quality by design concept is well understood for pharmaceutical manufacturing machinery's and process .Quality by design concept not only demands machinery and process disigning for quality but also puts stress on designing chemistry of your product so as to build a far better quality product.

Quality by design concept requires that the quality of a pharmaceutical product should be inbuilt , and the designing of process , machinery , and formulation should yield the final product of best quality ,and its quality is not dependant on later inspection and controls , but it is getting produced as per you plan .

1.Planing the quality2.Design the quality

Example 1Design a machinery with auto sampler , which will provide you a samples of your final product automatically , from all level for all time intervals , which represents complete batch and process of a pharmaceutical dosage form , this provides better accuracy of control , than human inspections.

Quality by design concept requires that not only machinery but other aspects of your formulations are needed to be designed to get quality of final product.

This is a best idea Quality by design for pharmaceuticals manufactured.

You have the ability to design your formulation which should yield best quality final product.

You have to plan your quality of final product while you are designing your formulation.Instead of putting stress on in process quality checking’s and inspections

This is what chemistry part of guidelines says.

Example 2I will like to give an example how you can design a formulation to yield best quality.Consider your final product is stable at PH 5.5, and a little fluctuation in final PH of your product gives you lot of problems .

While adjusting the final PH , your formula has given buffering agents quantities just sufficient to adjust the PH , and manufacturing person has assess to more than required quantity of buffering agent.

You have opportunity to design the quality here, by limiting the quantities of buffering agents.

Fix the quantity of the Buffering agent in the range of limit of +0.3 for final product

Now you have limited the access of manufacturing pharmacist to usage of buffering agent, he

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will use just sufficient quantity, and not quantity sufficient to adjust the PH of your final product.

This requires pilot as well as actual validations, and one it is set, your product will not have fluctuations in PH in wider range this will be always in the very small range of +0.3

This is true for other aspects of formulations too.

Putting limit on impurities in Raw material

Say a raw material is very critical for your pharmaceutical product.You get this material which complies the pharmacopoeial limit for impurities.But give lot of problems while in actual process.

You can design your limit of passing of this material test for impurities in the more strict range than that of pharmacopoeia.

You can develop your own method to analyze these impurities in the raw martial itself in better way so that you can ask your raw material manufacturer to make the material with your limit.

There are lots of tests which you can design to get best quality pharmaceutical product .

GUIDELINES FOR WRITING STANDARD OPERATING PROCEDURES

We are providing here details regarding how to write a standard operating procedure SOP for a WHO GMP Pharmaceutical Manufacturing unit. I am giving here a example SOP which will give you a exact idea ,so that you can write SOP of your company your self. I am keeping an example of a microbiology department for this purpose.

STANDARD OPERATING PROCEDURESOP No001Page 2 of 4Version: 1.4Date: 02/09/2008Revise by: 02/09/2011Written by: MartinRevised by : MartinAuthorised by:MartinThis is a guide to the format & writing content for including in a Standard Operating Procedures prepared in Microbiology & Biotechnology Departments.Use clear, simple, direct wording in short sentencesWrite procedures as chronological sequencesUse ‘shall’ or ‘must’ for mandatory actions and ‘should’ for advisory actionsProcedures should reflect current practiceIf any section is not applicable to the procedure, include “N/A” under the heading –DO NOT leave blank.The final SOP should consist, as far as possible, of one single electronic master file.A Standard Operating Procedure begins with an Introduction and does not include a preamble.1. Introduction: (what the intention of SOP )This introduction part provides background information on the procedure given in theSOP. This may include the reason for carrying out a certain task, a brief explanation of theinteractions or theory behind a particular procedure or tast or process, and when it may be

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appropriate to conduct the procedure described.Eg: The introduction for a SOP on ‘Protein Electrophoresis’:This SOP discusses the procedure and safety guidelines for electrophoresis of Proteins.When an electric charge is applied to an agarose gel, Proteins migrates through the gel matrix at a rate inversely proportional to the log10 of the number of amino acids and (if it is a DNA then it is number Bases).and depending up on the moleculer structure ,Super-helical, nicked circular, and linear DNA migrate at different rates relative to each other, and the relative mobility varies depending on many factors. DNA is visualised by the addition of a dye that intercalates between the stacked base pairs of the DNA molecule. Upon exposure to light of a specific wavelength, DNA-dye complexes emit fluorescent or luminescent light. Traditionally ethidium bromide dye has been used to visualise DNA. However, ethidium bromide is a strong mutagen and is being replaced by new non-mutagenic dyes with similar properties. SYBR Safe, a non-toxic dye, should now be used in place of ethidium bromide in this laboratory.2. Scope(where this SOP applied)This section states the circumstances under which the SOP is applied. Mention should be made of the extent or limitations of the SOP. If applicable, refer to associated regulatory or legislative information related to the work area or procedure described in the SOP.Eg 1: This procedure applies to all staff in the Department of Microbiology .and to any visitors working in the Department.Eg 2: This SOP sets out procedures for the cleaning, disinfection and sterilization of instruments and equipment, and maintenance of associated environments in a research laboratory. It may be suitable for application to instruments and equipment use in a veterinary practice. It does not apply to items intended by the manufacturer for single use only, nor to items that may be contaminated with unconventional infective agents, eg. Creutzfeldt.3. SafetyThis section must include all warnings of safety risks associated with performing theprocedure. These include but are not restricted to:· Any general precautions or issues that need to be taken into consideration.· Chemical Hazards: obtaining and reading of any relevant MSDSs, general or specialstorage conditions; licences and permits required.· Physical Hazards: RSI issues, use of trolleys, carrying of materials/loads, etc.· Radiation Hazards: monitoring, wearing of badges, details of shielding required.· Biological hazards: use of Class II cabinets; aerosol production;requirements as determined by who guidelines and expanded for OGTR certified and QAP accredited laboratories.· Use of PPE and any extra items that are identified as needed for the procedure.· Accidents and spills: clearly stated instructions as to the steps that need to be taken,precautions required and the correct method of “mopping” up anddisposal. First-aid procedure if applicable. Reporting procedure to supervisor and/orDepartment Safety Officer, using Incident Reports .4. Licences and PermitsThis section details all permits and licences that must be obtained before the procedure iscarried out. All permits and licences must be valid. Conditions required to comply with thepermits and licences should be noted on the SOP.Permits and Licences may include:Quarantine Approved Premises Certifications,licence for work and certification for facility, Poisons Licence and Poisons Control Plan, Dangerous Goods notification, who guidelines , etc5. Training and Competency· List all training needs required for the SOP and pre-requisites (ie. training in otherprocedures or items of equipment, knowledge of other SOPs) required for this procedure.Eg 1: Subculture of Microorganisms (non-pathogenic): The trainee must have already mastered an understanding of and have been given instruction in the use of asceptic technique.Eg 2: Use of Departmental FACS Machine: Users are required to be registered and must undergo training by the FACS Facility Manager to obtain registration.· Records must be kept of the personnel trained against this procedure. State where training

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records are kept.· The trainee must be assessed to determine if they are competent to perform theprocedure. Competency may be assessed by close observation of the trainee by anapproved trainer along with either a verbal exam or completion of a written assessmentby the trainee. The method by which competency is determined should be stated in thissection, eg. by observation, written quiz, oral examination, continuous record of correctresults, etc.6. Risk AssessmentsRisk assessments must be performed on any procedure that has an element of hazard.These assessments must be carried out by a staff member that has been trained in Risk Management (courses run by Faculty EHS Officer). Risk assessments should be kept as part of a Work Group Risk Register. Any assessments associated with a SOP should be referenced in the Risk Assessments section of the SOP, and should be attached to a hardcopy of the SOP document. If the SOP is to be stored as an electronic file only, then the risk assessments should be attached as part of the electronic copy of the SOP.7. Equipment and Maintenance / Handling and Storage / LabellingIdentify any special equipment used, describe location of equipment, location of instructionmanuals and any particular cleaning strategies. Service and maintenance details may also beincluded here. Alternatively, use this place to describe the storage and handling of chemicals/ biologicals, etc. State any special handling and transport procedures.Eg: Transporting a gel around department requires microbiological gel to be placed in a sealed container and one glove removed to avoid contaminating doors and lifts.Give details of any specific labelling required. A template or picture of the label can beincluded8. Operating ProceduresThe operating instructions or methodology must be written in a recipe-like manner – anordered list of clear, concise instructions or action steps.If applicable include:· Location where procedure will be done (eg. lab, bench, Biosafety cabinet, fume hood).· Labelling requirements at the steps where the need arises.· Troubleshooting information.· Clear instructions on cleaning and/or decontaminating work area, equipment and othermaterials used in the procedure.· State any routine maintenance requirements.9. Controls and CalibrationsAny internal or external quality control procedures or issues should be documented here.Provide any calibrations required for specific items (pH meter, micropipettes). Routine stepsshould also be included at the appropriate step in Section 8.Waste DisposalState specific waste disposal procedures for all items in the SOP. Include type of wastecontainers to be used and any special transport or labelling requirements.11. Relevant Documents / ReferencesRelevant external documents and procedures may apply to the SOP. Examples: WHO Guidelines,website, manufacturer’s operating instructions, scientific literature.List complete details of any external documents or websites relevant to or required for theSOP. Risk assessments applicable to the SOP are listed in Section 6.12. Signage / Summaries / TemplatesAny signs or summaries specifically relating to the SOP should be included here. Thisincludes simple step-by-step notices, warning signs, and templates for use in conjunctionwith the SOP, eg. for recording data or carrying out audits. Include information such as thenumber of copies of a sign or notice that needs to be printed, if these need to be laminated,and where these need to be displayed in appropriate areas or on relevant equipment.13. Appended MaterialIf the SOP is to be stored as a hardcopy with appended documents (which do not form part ofthe electronic SOP file), then a detailed list of all appended material is to be recorded in this

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section. This acts as a check in case this material is separated from the SOP, and aids inassessing the complete SOP when revision is required.The entire SOP, including appended items, should be kept as one complete document.Document control details (ie. SOP number, version, date, etc) should be shown on all the pages of a SOP, including the pages which contain appended material.I hope this article on sop will help , i have kept a vision to provide you all detailed knowledge on WHO guideline for pharmaceutical manufacturing.Following are some of articles which;will be useful for you in further understanding of aspects of sterile dosage form manufacturing 

Recommendations for Process Design 

Process Design In pharmaceutical manufacturing process design is the activity of defining the commercial

manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that

can consistently deliver a product that meets its quality attributes. 

Also see General Considerations for Process Validation and Recommendations 

Also see ( process validation in pharma ) 

1. Building and Capturing Process Knowledge and UnderstandingGenerally, early process design experiments do not need to be performed under the CGMP conditions required for drugs intended for commercial distribution that are manufactured during Stage 2 (process qualification) and Stage 3 (continued process verification). They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH Q10 Pharmaceutical Quality System. Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use or adaptation later in the lifecycle of the process and drug product. Although often performed at small-scale laboratories, most viral inactivation and impurity clearance studies cannot be considered early process design experiments. Viral and impurity clearance studies intended to evaluate and estimate product quality at commercial scale should have a level of quality unit oversight that will ensure that the studies follow sound scientific methods and principles and the conclusions are supported by the data. Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. Process information available from product development activities can be leveraged in the process design stage. The functionality and limitations of commercial manufacturing equipment should be considered in the process design, as well as predicted contributions to variability posed by different component lots, production operators, environmental conditions, and measurement systems in the production setting. However, the full spectrum of input variability typical of commercial production is not generally known at this stage. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability. Designing an efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained. Design of Experiment (DOE) studies can help develop process knowledge by revealing relationships, including multivariate interactions, between the variable inputs (e.g., component characteristics or process parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments conducted while maximizing knowledge gained. The results of DOE studies can

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provide justification for establishing ranges of incoming component quality, equipment parameters, and in-process material quality attributes. US FDA mentioned in its guidelines onprocess validation that it does not generally expect manufacturers to develop and test the process until it fails. Other activities, such as experiments or demonstrations at laboratory or pilot scale, also assist in evaluation of certain conditions and prediction of performance of the commercial process. These activities also provide information that can be used to model or simulate the commercial process. Computer-based or virtual simulations of certain unit operations or dynamics can provide process understanding and help avoid problems at commercial scale. It is important to understand the degree to which models represent the commercial process, including any differences that might exist, as this may have an impact on the relevance of information derived from the models. It is essential that activities and studies resulting in process understanding be documented. Documentation should reflect the basis for decisions made about the process. For example, manufacturers 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 when the design is revised or the strategy for control is refined or changed. 

2. Establishing a Strategy for Process Control Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during pharmaceuticals manufacturing (and so reduce its impact on the output), or combine both approaches. Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points (§ 211.110(c)). Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained. It is expected that controls to include both examination of material quality and equipment monitoring. Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios: 1. When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) or 2. When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified. 

These controls are established in the master production and control records (see § 211.186(a) and (b)(9)). More advanced strategies, which may involve the use of process analytical technology (PAT), can include timely analysis and control loops to adjust the processing conditions so that the output remains constant. Manufacturing systems of this type can provide a higher degree of process control than non-PAT systems. In the case of a strategy using PAT, the approach to process qualification will differ from that used in other process designs.  PAT ― A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.

The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation.Also see ( process validation in pharma ) FDA guideline

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Terminology and definitions

Capability of a process: Ability of a process to produce a product that will fulfill the requirements of that product. The concept of process capability can also be defined in statistical

terms. (ISO 9000:2005) 

Commercial manufacturing process: The manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). the term

commercial manufacturing process does not include clinical trial or treatment IND material. 

Concurrent release: Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the lot release criteria established in the protocol, but before

the entire study protocol has been executed. 

Continued process verification: Assuring that during routine production the process remains in a state of control. 

Performance indicators: Measurable values used to quantify quality objectives to reflect the performance of an organization, process or system, also known as performance metrics in

some regions. (ICH Q10) 

Process design: Defining the commercial manufacturing process based on knowledge gained through development and scale-up activities. 

Process qualification: Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing. 

See here. Process validation

Quality: The degree to which a set of inherent properties of a product, system, or process fulfils requirements. (ICH Q9) 

State of control: A condition in which the set of controls consistently provides assurance of continued process performance and product quality. (ICH Q10)

FDA guidelineAlso see Aspects of Validation of Aseptic Process and Sterilisation , Sterilization of Equipment, Containers, and Closures  

What is pharmaceutical product information manual (Pharmaceutical product dossier) for registration of   pharmaceutical prodct to foreign contries --------------------------------------------------------------------------------------------------------

Process Validation Series    

Process validation aspects of Analytical Methodology. 

Process Validation Stage 3 The Continued Process Verification. 

Process Validation : Process Qualification and Process Performance Qualification (PPQ) 

Process Design and Process Validation Recommendations  

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Process validation and its regulatory, statutory requirements. 

Process Validation and Drug Quality Approach to Process Validation. 

General Considerations for Process Validation and Recommendations

Capability of a process: Ability of a process to produce a product that will fulfill the requirements of that product. The concept of process capability can also be defined in statistical terms. (ISO 9000:2005) 

Commercial manufacturing process: The manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). the term commercial manufacturing process does not include clinical trial or treatment IND material. 

Concurrent release: Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the lot release criteria established in the protocol, but before the entire study protocol has been executed. 

Continued process verification: Assuring that during routine production the process remains in a state of control. 

Performance indicators: Measurable values used to quantify quality objectives to reflect the performance of an organization, process or system, also known as performance metrics in some regions. (ICH Q10) 

Process design: Defining the commercial manufacturing process based on knowledge gained through development and scale-up activities. 

Process qualification: Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing. 

See here. Process validation

Quality: The degree to which a set of inherent properties of a product, system, or process fulfils requirements. (ICH Q9) 

State of control: A condition in which the set of controls consistently provides assurance of continued process performance and product quality. (ICH Q10)

Validation (drug manufacture)From Wikipedia, the free encyclopedia

In the pharmaceutical, medical device, food, blood establishments, tissue establishments, and clinical trials

industries, validation is the documented act of demonstrating that a procedure, process, and activity will

consistently lead to the expected results. It often includes the qualification of systems and equipment. It is a

requirement for good manufacturing practices and other regulatory requirements. Since a wide variety of

procedures, processes, and activities need to be validated, the field of validation is divided into a number of

subsections including the following:

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Cleaning validation

Process validation

Analytical method validation

Computer system validation

Similarly, the activity of qualifying systems and equipment is divided into a number of subsections including the

following:

Design qualification (DQ)

Component qualification (CQ)

Installation qualification (IQ)

Operational qualification (OQ)

Performance qualification (PQ)

Contents

  [hide] 

1   History

2   Reasons for validation

3   Validation Master Plan

4   The validation process

5   Computer System Validation

6   Scope of Computer Validation

7   Risk Based Approach To Computer Validation

8   See also

9   References

[edit]History

The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and

Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals (Agalloco 1995). It was proposed in

direct response to several problems in the sterility of large volume parenteral market. The first validation activities

were focused on the processes involved in making these products, but quickly spread to associated processes

including environmental control, media fill, equipment sanitization and purified water production.

The concept of validation was first developed for equipment and processes and derived from the engineering

practices used in delivery of large pieces of equipment that would be manufactured, tested, delivered and accepted

according to a contract (Hoffmann et al. 1998). The use of validation spread to other areas of industry after several

large-scale problems highlighted the potential risks in the design of products. The most notable is the Therac-

25 incident, (Leveson & Turner 1993). Here, the software for a large radiotherapy device was poorly designed and

tested. In use, several interconnected problems led to several devices giving doses of radiation several thousands

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of times higher than intended, which resulted in the death of three patients and several more being permanently

injured.

In 2005 an individual wrote a standard by which the transportation process could be validated for cold chain

products.[citation needed] This standard was written for a biological manufacturing company and was then written into the

PDA's Technical Report # 39, thus establishing the industry standard for cold chain validation. This was critical for

the industry due to the sensitivity of drug substances, biologics and vaccines to various temperature conditions. The

FDA has also been very focused on this final area of distribution and the potential for a drug substances quality to

be impacted by extreme temperature exposure.

[edit]Reasons for validation

Validation is "Establishing documented evidence that provides a high degree of assurance that a specific process

will consistently produce a product meeting its pre-determined specifications and quality attributes." (FDA 1987). A

properly designed system will provide a high degree of assurance that every step, process, and change has been

properly evaluated before its implementation. Testing a sample of a final product is not considered sufficient

evidence that every product within a batch meets the required specification

[edit]Validation Master Plan

The Validation Master Plan is a document that describes how and when the validation program will be executed in a

facility. Even though it is not mandatory, it is the document that outlines the principles involved in the qualification of

a facility, defines the areas and systems to be validated and provides a written program for achieving and

maintaining a qualified facility with validated processes. It is the foundation for the validation program and should

include process validation, facility and utility qualification and validation, equipment qualification, cleaning and

computer validation. The regulations also set out an expectation that the different parts of the production process

are well defined and controlled, such that the results of that production will not substantially change over time.

[edit]The validation process

Figure 1: Traditional Qualification Process (adapted from the typical V-Model)

The validation process consists of identifying and testing all aspects of a process that could affect the final test or

product. Prior to the testing of a process, the system must be properly qualified. Qualification includes the following

steps: (These steps are common practice for equipment IQ, OQ and PQ).

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Design qualification (DQ)- Defines the functional and operational specification of the instrument, program,

or equipment and details the rationale for choosing the supplier.

Installation qualification (IQ) – Demonstrates that the process or equipment meets all specifications, is

installed correctly, and all required components and documentation needed for continued operation are

installed and in place.

Operational qualification (OQ) – Demonstrates that all facets of the process or equipment are operating

correctly.

Performance qualification (PQ) – Demonstrates that the process or equipment performs as intended in a

consistent manner over time.

Component qualification (CQ) – is a relatively new term developed in 2005. This term refers to the

manufacturing of auxiliary components to ensure that they are manufactured to the correct design criteria. This

could include packaging components such as folding cartons, shipping cases, labels or even phase change

material. All of these components must have some type of random inspection to ensure that the third party

manufacturer's process is consistently producing components that are used in the world of GMP at drug or

biologic manufacturer.

There is often overlap between Installation, Operational, and Performance Qualification and sometimes these are

performed simultaneously.

Figure 2: OPQ Validation Process (adapted from the typical V-Model)

This combined testing of OQ and PQ phases is sanctioned by the European Commission Enterprise Directorate-

General within ‘Annex 15 to the EU Guide to Good Manufacturing Practice guide’ (2001, p. 6) which states that:

"Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction

with OQ."

[edit]Computer System Validation

This requirement has naturally expanded to encompass computer systems used both in the development and

production of, and as a part of pharmaceutical products, medical devices, food, blood establishments, tissue

establishments, and clinical trials. In 1983 the FDA published a guide to the inspection of Computerized Systems in

Pharmaceutical Processing, also known as the 'bluebook' (FDA 1983). Recently both the American FDA and the

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UK Medicines and Healthcare products Regulatory Agency have added sections to the regulations specifically for

the use of computer systems. In the UK, computer validation is covered in Annex 11 of the EU GMP regulations

(EMEA 2011). The FDA introduced 21 CFR Part 11 for rules on the use of electronic records, electronic signatures

(FDA 1997). The FDA regulation is harmonized with ISO 8402:1994 (ISO 1994), which treats "verification" and

"validation" as separate and distinct terms. On the other hand, many software engineering journal articles and

textbooks use the terms "verification" and "validation" interchangeably, or in some cases refer to software

"verification, validation, and testing (VV&T)" as if it is a single concept, with no distinction among the three terms.

The General Principles of Software Validation (FDA 2002) defines verification as "Software verification provides

objective evidence that the design outputs of a particular phase of the software development life cycle meet all of

the specified requirements for that phase." It also defines Validation as "Confirmation by examination and provision

of objective evidence that software specifications conform to user needs and intended uses, and that the particular

requirements implemented through software can be consistently fulfilled". The software validation guideline states:

“The software development process should be sufficiently well planned, controlled, and documented to detect and

correct unexpected results from software changes." Annex 11 states "The validation documentation and reports

should cover the relevant steps of the life cycle."

Weichel (2004) recently found that over twenty warning letters issued by the FDA to pharmaceutical companies

specifically cited problems in Computer System Validation between 1997 and 2001.

Probably the best known industry guidance available is the GAMP Guide, now in its fifth edition and known as

GAMP5 published by ISPE (2008). This guidance gives practical advice on how to satisfy regulatory requirements.

[edit]Scope of Computer Validation

The definition of validation above discusses production of evidence that a system will meet its specification. This

definition does not refer to a computer application or a computer system but to a process. The main implications in

this are that validation should cover all aspects of the process including the application, any hardware that the

application uses, any interfaces to other systems, the users, training and documentation as well as the

management of the system and the validation itself after the system is put into use. The PIC/S guideline (PIC/S

2004) defines this as a 'computer related system'. Much effort is expended within the industry upon validation

activities, and several journals are dedicated to both the process and methodology around validation, and the

science behind it (Smith 2001; Tracy & Nash 2002; Lucas 2003; Balogh & Corbin 2005).

[edit]Risk Based Approach To Computer Validation

In recent years, a risk-based approach has been adopted within the industry, where the testing of computer

systems (emphasis on finding problems) is wide-ranging and documented but not heavily evidenced (i.e. hundreds

of screen prints are not gathered during testing). Annex 11 states "Risk management should be applied throughout

the lifecycle of the computerised system taking into account patient safety, data integrity and product quality. As

part of a risk management system, decisions on the extent of validation and data integrity controls should be based

on a justified and documented risk assessment of the computerised system."

The subsequent validation or verification of computer systems targets only the "GxP critical" requirements of

computer systems. Evidence (e.g. screen prints) is gathered to document the validation exercise. In this way it is

assured that systems are thoroughly tested, and that validation and documentation of the "GxP critical" aspects is

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performed in a risk-based manner, optimising effort and ensuring that computer system's fitness for purpose is

demonstrated.

The overall risk posed by a computer system is now generally considered to be a function of system complexity,

patient/product impact, and pedigree (Configurable-Off-The-Shelf or Custom-written for a certain purpose). A lower

risk system should merit a less in-depth specification/testing/validation approach. (e.g. The documentation

surrounding a spreadsheet containing a simple but "GxP" critical calculation should not match that of a

Chromatography Data System with 20 Instruments)

Determination of a "GxP critical" requirement for a computer system is subjective, and the definition needs to be

tailored to the organisation involved. However in general a "GxP" requirement may be considered to be a

requirement which leads to the development/configuration of a computer function which has a direct impact on

patient safety, the pharmaceutical product being processed, or has been developed/configured to meet a regulatory

requirement. In addition if a function has a direct impact on GxP data (security or integrity) it may be considered

"GxP critical".

[edit]See also

GxP

Good Manufacturing Practice  (GMP)

Good Automated Manufacturing Practice  (GAMP)

Verification and Validation

Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme

Regulation of therapeutic goods

United States Pharmacopeia

[edit]References

This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please improve this article by introducing more precise citations. (April 2009)

Health Canada Validation Guidelines

Agalloco, J. (1995), 'Validation: an unconventional review and reinvention', PDA J Pharm Sci Technol., vol.

49, no. 4, pp. 175–179.

Akers, J. (1993), 'Simplifiying and improving Process Validation', Journal of Parenteral Science and

Technology, vol. 47, no. 6, pp. 281–284.

ASTM  E2537 Guide for Application of Continuous Quality Verification for Pharmaceutical and

Biopharmaceutical Manufacturing

Balogh, M. & Corbin, V. (2005), 'Taming the Regulatory Beast: Regulation vs Functionalism',

Pharmaceutical Technology Europe, vol. 17, no. 3, pp. 55–58.

EMEA (1998), EUDRALEX Volume 4 – Medicinal Products for Human and Veterinary Use : Good

Manufacturing Practice, European Medicines Agency, London

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European Commission Enterprise Directorate-General (2001), Final Version of Annex 15 to the EU Guide

to Good Manufacturing Practice, Qualification and Validation, Brussels. European Commission Enterprise

Directorate-General.

FDA (1983), Guide to Inspection of Computerised Systems (The Blue Book), US Food and Drug

Administration, Maryland, USA.

US FDA: Guideline on general principles of Process Validation

US FDA (2002): General Principles of Software Validation; Final Guidance for Industry and FDA Staff

Part 11: Electronic Records; Electronic Signatures,Code of Federal Regulations

Garston Smith, H. (2001), 'Considerations for Improving Software Validation', Journal of Validation

Technology, vol. 7, no. 2, pp. 150–157.

Hoffmann, A., Kahny-Simonius, J., Plattner, M., Schmidli-Vckovski, V., & Kronseder, C. (1998), 'Computer

system validation: An overview of official requirements and standards', Pharmaceutica Acta Helvetiae, vol. 72,

no. 6, pp. 317–325.

ISO (1994), ISO 8402:1994: Quality management and quality assurance—Vocabulary, International

Organization for Standardization, Geneva, Switzerland

ISPE (2008), GAMP5: Risk Based Approach to Computer Compliance, International Society for

Phamraceutical Engineers, Tampa, FL.*Leveson, N. G. & Turner, C. S. (1993), 'An investigation of the Therac-

25 accidents', Computer, vol. 26, no. 7, pp. 18–41.

IT Pharma Validation Europe : News and Updates on Computer System Validation and Infrastructure

Qualification – e.g. EudraLex Volume 4 – Annex 11 computerised systems – revision January 2011

Lopez, Orlando (2002), “21 CFR Part 11 – A Complete Guide to International Compliance,” published by

Sue Horwood Publishing Limited.

Lucas, I. (2003), 'Testing Times in Computer Validation', Journal of Validation Technology, vol. 9, no. 2,

pp. 153–161.

McDowall, R. D. (2005), 'Effective and practical risk management options for computerised system

validation', The Quality Assurance Journal, vol. 9, no. 3, pp. 196–227.

Parker G, (2005) ‘Developing Appropriate Validation and Testing Strategies’ Presented for Scimcon Ltd at

the Thermo Informatics World Conference. North America.

PIC/S (2004), Good Practices for Computerised Systems in Regulated "GXP" Environments, Report PI

011-2, Pharmaceutical Inspection Convention, Geneva

Powell-Evans, K. (1998), 'Streamlining Validation', Pharmaceutical Technology Europe, vol. 10, no. 12,

pp. 48–52.

Segalstad, S.H (2008), ‘International IT Regulations and Compliance: Quality Standards in the

Pharmaceutical and Regulated Industries', John Wiley & Sons , pp. 157 – 178.

Smith, H. G. (2001), 'Considerations for Improving Software Validation, Securing better assurance for less

cost', Journal of Validation Technology, vol. 7, no. 2, pp. 150–157.

Swartz, M. (2006) ‘Analytical Instrument Qualification’, Avanstar [online], available

at: http://www.advanstar.com/test/pharmascience/pha-sci_supp-promos/phasci_reg_guidance/articles/

Instrumentation1_Swartz_rv.pdf (Accessed 29 March 2009).

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Tracy, D. S. & Nash, R. A. (2002), 'A Validation Approach for Laboratory Information Management

Systems', Journal of Validation Technology, vol. 9, no. 1, pp. 6–14.

Validating Software used for the Pharmaceutical Industry. (2007). Retrieved July 6, 2009,

from http://www.plainsite.net/validation/validation.htm

Weichel, P. (2004), 'Survey of Published FDA Warning Letters with Comment on Part 11 (21 CFR Part 11)',

Journal of Validation Technology, vol. 11, no. 1, pp. 62–66.

WHO Technical Report Series, No. 937, 2006. Annex 4. Appendix 5. 2006

Wingate, G.A.S. (2004), 'Computer Systems Validation: Quality Assurance, Risk Management, and

Regulatory Compliance for the Pharmaceutical and Healthcare Industry', Interpharm Press.