validation

ValidationSubmitted by:Sharath . H . NM.PharmaSubmitted to :Mr.Manish Majumder,Associate professor Dept. of pharmaceutical analysis

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IndexIntroduction & scopes of ValidationCleaning validationPersonal validationTechnology transfer

VALIDATION

Introduction Validation is " a process of establishing documentary evidence demonstrating that a procedure, process, or activity carried out in production or testing maintains the desired level of compliance at all stages.

Here the desired results are established in terms of specifications for out come of the process. Qualification of systems and equipment is therefore a part of process of validation. It is a requirement of food and drug, pharmaceutical regulating agencies like FDA's good manufacturing practices guidelines.

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:>Equipment validation>Facilities validation>HVAC system validation.>Cleaning validation>Process Validation.>Analytical method validation>Computer system validation>Packaging 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)

Scope of validation 1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in timely manner. Management and persons responsible for Quality Assurance should be involved. 2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed. 3 There should be proper preparation and planning before validation is performed. There should be a specific programme for validation activities.

4 Validation should be performed in a structured way according to the documented procedures and protocols. 5 Validation should be performed for (1) new premises, equipment, utilities and systems, and processes and procedures, (2) at periodic intervals, and (3) when major changes have been made.

6 Validation should be performed in accordance with written protocols. The outcome of the validation should be reflected in written reports. 7 Validation can be prospective, concurrent, or retrospective, depending on when validation is performed. 8 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to show consistency. Worst case situations should be considered.

Cleaning validationCleaning validation in the pharmaceutical industry has been a topic ofever-increasing interest and scrutiny in recent Food and DrugAdministration (FDA) inspections. The validation of procedures used toclean the equipment employed during the various steps of a manufacturing process is a clear requirement of current Good Manufacturing Practice(cGMP).

DefinitionCleaning validation may be defined as " a process of attaining & documenting sufficient evidence to give reasonable assurance , given the current state of science & technology, that the cleaning process under consideration does, and\or will do ,what it purports to do".

Objectives1.The objective of the cleaning validation is to verify the effectiveness of the cleaning pprocedure for removal of product residues, degradation products, preservatives, excipients, and/or cleaning agents as well as the control of potential microbial contaminants.

2. In addition one need to ensure there is no risk associated with cross contamination of active ingredients. Cleaning procedures must strictly follow carefully established and validated methods.

It is necessary to Validate Cleaning procedures for the following reasons:Pharmaceutical products and API can be contaminated by other pharmaceutical products, cleaning agent & microbial contamination.It is regulatory requirement in pharmaceutical product manufacture the concern is the same-assurance that equipment is clean and that product quality and safety are maintained.It is also assure from an internal control and compliance point of view the quality of manufacture.To protect product integrity To reuse the equipment

Other objectivesSolvent reduction, Shorter cleaning times, increased equipment- Utilization, extension of equipment life, multiproduct- Facilities, worker safety, and cost- eff

Various steps involved

- Visual inspection-Rinse water sampling and analysis-Surface sampling & analysis-Method selection-Solvents-Sampling methods-Residue detection-Analytical Evaluation-Worst- case determination- Acceptance criteria

Visual inspection Active product contact parts of the equipment are individually examined (wherever possible) for cleanliness. This visual inspection allows the early localization and identification of any inadequacies in the cleaning procedure.

Qualitative dependent upon inspection and item sampled.

Rinse water sampling and analysis Analysis can be quantitative, using pH, conductivity, particle count,microbial count, Total Organic Carbon (TOC) determination, spectrophotometry, bioassays or limulus amebocyte lysate for pyrogens. Recovery factor is uncertain; it involves dilution

.Surface sampling from coupons Quantitative. Depends on whether coupons are equivalent to the surface of interest. Requires removing coupons from the system.

Method Selection

Whenever possible, each piece of equipment should be dismantled into its individual components after cleaning and each part should be individually tested for cleanliness. In this manner, any inadequacy in the cleaning process will be more readily identified and localized.

Solvents

Aqueous or organic solvents used in the cleaning procedure,should be sufficient to remove residues, and at the same time,should be minimized to reduce the risk of reaction with or damageto the equipment, or the over-dilution of the residue and the result-ant loss of analytical sensitivity.Samples should be collected in clean or sterile containthis

Sampling MethodsThe sampling method selection for cleaners, involves choosing between rinse water sampling, swabbing surfaces, coupon sampling, or placebo sampling. Rinse water sampling involves taking a sample of an equilibrated post-final rinse that has been re-circulated over all surfaces. Rinse samples should be correlated to a direct measuring technique such as swabbing.

Residue DetectionSelecting a method to detect cleaner residues can involve specific methods for specific cleaner ingredients such as: HPLC), ion selective electrodes, flame photometry, derivative UltraViolet (UV) spectroscopy, Thin Layer Chromatography, enzymatic detection, and titration. It can also involve non-specific methods that detect the presence of a blend ofingredients such as: TOC, pH, and conductivity.

Analytical EvaluationAnalytical validation of the cleaning procedure should be performed after the approval of visual inspection (absence of stains or any materiel residue). The specificity, sensitivity, and percentage of recovery of the test method should be adequate to meet acceptance criteria.

Worst-Case DeterminationWorst-case determination of cleaning validation is a crucial step in defining contamination limits and in cleaning procedure efficacy. A worst-case determination study should be based on: active productsolubility; active product toxicity; smallest batch size that can be manufactured using the equipment concerned; the maximum daily dose of this product.

Acceptance CriteriaIn determining the final acceptance criteria for a cleaning validation exercise, the calculation of the acceptable level of contaminant in the next product maximum therapeutic patient dose is of primary importance. Acceptance criteria are established by considering the contaminant type, the facility, and the risk to the operator, product, and patient.

Cleaning Analytical Method Validation The following sections should be included: Scope Describe the active product (s) that could be evaluated by the method.

Describe the method followed to determine the acceptance criteria theThe major and critical acceptance criteria to be mentioned are as follows: active product recovery percentage and active percentage(contaminant) g per cm2 or g of active residual (contaminant) per maximum daily dose units of next product.

Method

Description of analytical methods used: standard preparation, sample preparation, analytical equipment used, analytical parameters, equipment parameter, sample volume, materials used, and the determination of the following values (which are specific to the analytical method and are relative for each active product):

Precision Accuracy Limit of Detection Limit of Quantitation (LoQ) Linearity (where appropriate, linearity of detector response for standard solution over a range of concentrations) Recovery percentage Absence of interference between swab materials and active product Absence of interference between solvent and active product

Personal validation

PERSONAL VALIDATION

The basic purpose of personal validation is evaluate and measure the work behavior, quality of work, job knowledge with a focus on the accuracy in the assigned work by analyzing the work characteristics, effective communication & positive relationship that a personnel display at work place. SCOPEThe Personnel Validation covers all aspects of GMP which includes performance dimension

The regulatory guidelines talks about many things, about people.some of these are as follows:1.people must be qualified,experienced & trained.2. They must be sufficient in number.3. Their job responsibilities must be well explained to them & monitered.4. They must be highly motivated.

1.Qualification,Experience & Training(a). Qualifications:W.H.O giidelines on GMP give some guidelines on the qualificationsFor eg: the education should include study of an appropriate combination of chemistry( analytical & organic) or biochemistry, chemical engineering, microbiology, PST,pharmacology & toxicology& other related sciences.

(b) Training of Employees:A person is called " a trained person ", when he has appropriate knowledge, skill and attitude.

(c) Sufficient number of people: According to guidelines there should be sufficient number of people to carry out the tasks which manufactures are responsible".

(d) Ability to perform given task at given level:Peoples are trained to perform different levels of operations to perform the designated jobs.

(e) Appropriate managerial skills:Managerial skills carryout functions of planning, organising , staffing, leading & controlling.

2.Responsibilities & key personnel(a). Responsibilities & Job description:In a pharmaceutical plant different jobs are performed, so it be comes important to have clarity & specification over his job.

(b). Key personnel:Key personals are position in the organisation,which have a direct impact on the working organisation & quality of products produced.

For eg:-The head of Quality control-The head of production.-Joint responsibities of Q.C. & production heads.

3.Personal hygiene & clothing

According to guidelines , we need to maintain high level of hygienic conditions in manufacturing environment. Few of guidelines mentioned below:

-High standards of personal cleanliness should be maintained, stringent rules followed for manufacturing of sterile products.

-Habit of hand washing must be inculcated in all the employees.

-Eating, drinking, smoking, storage of food should not be allowed within manufacturing areas.

-Direct contact of operator hands with any part of equipment should be avoided.

-Visual inspection staff should pass an annual eye inspection.

-Only personal authorised by supervisory personal shall enter those areas of buildings & facilities.

LEGAL ASPECTS

Personal related legal aspects are covered in regulatory literature,only by M.C.C ,south africa guidelines,W.H.O & schedule M of D & C act of India.

1.Schedule M of D & C act India: It says manufacturing should be done in supervision of competent technical staff with prescribed qualifications

W.H.O guidelines:

It says that key personnel responsible for supervising the manufacture & QC of pharmaceutical products should possess the qualification of a scientific education & practical experience required by national legislation.

3.M.C.C. South africa:

It says that

- The company & MD must register in pharmacy council.

-Pharmaceutical operations must be conducted under supervision of pharmacists displayed over main entrance.

- Duties like compounding, manufacturing, distribution & sale of medicines must be performed by pharmacists.

- Other legal requirementslike, labellings & packaging of medicines,maintaining records & registers, reporting errors, advertising can be carried out..

Documents required:

-Copies of drug licenses given by drug control authorities along with list of products permitted to be manufactured.-list of competent technical staff along with their copy of certificate of approval.

5.CONSULTANTS.Consultant is a person who provides expert advice professionly.Regulatory authorities allow, pharmaceutical manufacturer to seek such advice from consultents.(a). As per U.S.F.D.A1. It has identified certain ares for such advice eg.manufacture, processing, packaging & holding of products.

2.Such consultants must have sufficient educatiom,traimg & experiance or any combination.

3.Manufacture should maintain records of such consultants giving the following details:-Name,Address,Qualifications, Types of service provided.

(b). M.C.C South africa

- only in exceptional circumstances should persons be engaged part time or in a consultative capacity be appointef to key positions.

- Other datails remain same as given by U.S.F.D.A.Documents required

-Records of consultants, giving details of name, qualifications,address & type of consultancu provided.

Technology transfer

Introduction Transfer of processes to an alternative site occurs at some stage in the life-cycle of most products, from development, scale-up, manufacturing, production and launch, to the post-approval phase.

Transfer of technology is defined as a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites. It is a systematic procedure that is followed in order to pass the documented knowledge and experience gained during development and or commercialization to an appropriate, responsible and authorized party.

Technology transfer embodies both the transfer of documentation and the demonstrated ability of the receiving unit (RU) to effectively perform the critical elements of the transferred technology, to the satisfaction of all parties and any applicable regulatory bodies.

1 This document gives guidance in principle and provides general recommendations on the activities necessary to conduct a successful intra-or intersite transfer of technology as described in the Introduction to these guidelines. The intention is to address the basic considerations needed for a successful transfer in order to satisfy the regulatory authority defined for the transfer pradvice

2 The guidelines will be applied to manufacturing active pharmaceutical ingredients (APIs), manufacturing and packaging of bulk materials, manufacturing and packaging of finished pharmaceutical products (FPPs) and performing analytical testing.

3 The recommendations provided in these guidelines apply to all dosage forms but need to be adjusted on a case-by-case basis (e.g. by using risk management principles). Particularly close control of certain aspects will be required for certain formulations such as sterile products, and metered-dose aerosols. WHO guidance on manufacture of specific pharmaceutical products will be useful in this regard.Scope

The guidelines address the following areas at the SU and the RU:- transfer of development and production (processing, packaging and cleaning); transfer of analytical methods for quality assurance and quality control;

skills assessment and training

organization and management of the transfer

assessment of premises and equipment

documentation and

qualification and validation.

Organization and management

1 Transfer comprises an SU and an RU. In some circumstances there may be an additional unit which will be responsible for directing, managing and approving the transfer.

2 There is a formal agreement between the parties, which specifies the responsibilities before, during and after transfer.

3 Organization and management of a successful technology transfer need to ensure that the main steps have been executed and documented as described in section .

4 There should be a project management plan which identifies and controls all the necessary activities identified at the start of the undertaking.

Production: transfer (processing, packaging circumstances

1 The RU should be able to accommodate the intended production capacity. If possible, it should be established at the outset whether the intention is to perform single-batch manufacture, continuous production or campaigns.

2 Consideration should be given to the level and depth of detail to be transferred to support production and any further process development and optimization at the RU as intended under the transfer project plan.

3 Consideration should be given to the technical expertise, site technology and site capabilities for the RU. It should be identified upfront by the SU of any process robustness issues so that plans may be put in place at the RU.

4 The SU and the RU should jointly develop a protocol for the transfer of relevant information related to the process under consideration from the SU to the RU, as well as the development of a comparable process at the RU.

Quality control: analytical method transfer

1 Transfer of analytical methods should accommodate all the analytical testing required to demonstrate compliance of the product to be transferred with the registered specification .

2 Analytical methods used to test pharmaceutical products, starting materials, packaging components and cleaning (residue) samples, if applicable, should be implemented at the testing laboratory before testing of samples for process validation studies is performed by the RU. Process validation samples may be tested at the RU, the SU or a third laboratory.

3 A protocol defining the steps should be prepared for transfer of analytical methods. The analytical methods transfer protocol should include a description of the objective, scope and responsibilities of the SU and the RU; a specification of materials and methods the experimental design and acceptance criteria; documentation (including information to be supplied with the results, and report forms to be used, if any); procedure for the handling of deviations; references; signed approval; and details of reference samples (starting materials, intermediates and finished products).

Premises and equipment Premises

1 The SU should provide information to the RU on the layout, construction and finish of buildings and services (heating, ventilation and air-conditioning (HVAC), temperature, relative humidity, water, power, and compressed air), which have an impact on the product, process or method to be transferred.

2 The SU should provide information on relevant health, safety and eenvironmental issues, including:

inherent risks of the manufacturing processes (e.g. reactive chemical hazards, exposure limits, fi re and explosion risks);

health and safety requirements to minimize operator exposure (e.g. atmospheric containment of pharmaceutical dust);

emergency planning considerations (e.g. in case of gas or dust release, spillage, fi re and firewater run-off); and

identification of waste streams and provisions for re-use, recyclingorr disposal.

Equipment

3 The SU should provide a list of equipment, makes and models involved in the manufacture, filling, packing and control of the product, process or method to be transferred, together with existing qualification and validation documentation.

Documentation

1 The documentation required for the transfer project itself is wide-ranging.

2 The documented evidence that the transfer of technology has been considered successful should be formalized and stated in a technology transfer summary report. That report should summarize the scope of the transfer, the critical parameters as obtained in the SU and RU (preferably in a tabulated format) and the final conclusions of the transfer. Possible discrepancies should be listed and appropriate actions, where needed, taken to resolve it.

Qualification and validationGeneral

.1 The extent of qualification and or validation to be performed should be determined on the basis of risk management principles.

Qualification and validation should be documented.

References :1.Analytical method development and validation by michel E Swartz2.Pharmaceutical Quality Assurance by Manohar.A.Potdar2.ICH 10 Pharmaceutical quality system.3.Good manufacturing guidelines.4.Validation Wikipedia.5.Internet source.

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