Validation of Cleaning Process

I. INTRODUCTION

Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.

This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable). Simultaneously, one must recognize that for cleaning validation, as with validation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.

This guide is intended to cover equipment cleaning for chemical residues only.

II. BACKGROUND

For FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillins or the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillin cross-contamination.

One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.

Some shipments of this pesticide contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced.

FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured potent steroid products as well as non-steroidal products using common equipment. This firm was a multi-use bulk pharmaceutical facility. FDA considered the potential for cross-contamination to be significant and to pose a serious health risk to the public. The firm had only recently started a cleaning validation program at the time of the inspection and it was considered inadequate by FDA. One of the reasons it was considered inadequate was that the firm was only looking for evidence of the absence of the previous compound. The firm had evidence, from TLC tests on the rinse water, of the presence of residues of reaction byproducts and degradants from the previous process.

III. GENERAL REQUIREMENTS

FDA expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address these different scenario. Similarly, if firms have one process for removing water soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed. Bulk pharmaceutical firms may decide to dedicate certain equipment for certain chemical manufacturing process steps that produce tarry or gummy residues that are difficult to remove from the equipment. Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a specific product. Any residues from the cleaning process itself (detergents, solvents, etc.) also have to be removed from the equipment.

FDA expects firms to have written general procedures on how cleaning processes will be validated.

FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.

FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.

FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.

FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an "acceptable level."

IV. EVALUATION OF CLEANING VALIDATION

The first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process. For example, at what point does a piece of equipment or system become clean? Does it have to be scrubbed by hand? What is accomplished by hand scrubbing rather than just a solvent wash? How variable are manual cleaning processes from batch to batch and product to product? The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company.

Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system will have one process for cleaning, however this will depend on the products being produced and whether the cleanup occurs between batches of the same product (as in a large campaign) or between batches of different products. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.

1. Equipment Design

Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type piping without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.

When such systems are identified, it is important that operators performing cleaning operations be aware of problems and have special training in cleaning these systems and valves. Determine whether the cleaning operators have knowledge of these systems and the level of training and experience in cleaning these systems. Also check the written and validated cleaning process to determine if these systems have been properly identified and validated.

In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.

Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.

Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

Subsequent to the cleaning process, equipment may be subjected to sterilization or sanitization procedures where such equipment is used for sterile processing, or for nonsterile processing where the products may support microbial growth. While such sterilization or sanitization procedures are beyond the scope of this guide, it is important to note that control of the bioburden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.

2. Cleaning Process Written

Procedure and Documentation

Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.

When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself which includes information about who cleaned it and when is valuable. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.

Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.

3. Analytical Methods

Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).

4. Sampling

There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.

a. Direct Surface Sampling - Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.

Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.

b. Rinse Samples - Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.

A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.

Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.

c. Routine Production In-Process Control

Monitoring - Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. This would be particularly true for the bulk drug substance manufacturer where reactors and centrifuges and piping between such large equipment can be sampled only using rinse solution samples. Any indirect test method must have been shown to correlate with the condition of the equipment. During validation, the firm should document that testing the uncleaned equipment gives a not acceptable result for the indirect test.

V. ESTABLISHMENT OF LIMITS

FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable. It is important to define the sensitivity of the analytical methods in order to set reasonable limits. Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.

Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.

VI. OTHER ISSUES

a. Placebo Product

In order to evaluate and validate cleaning processes some manufacturers have processed a placebo batch in the equipment under essentially the same operating parameters used for processing product. A sample of the placebo batch is then tested for residual contamination. However, we have documented several significant issues that need to be addressed when using placebo product to validate cleaning processes.

One cannot assure that the contaminate will be uniformly distributed throughout the system. For example, if the discharge valve or chute of a blender are contaminated, the contaminant would probably not be uniformly dispersed in the placebo; it would most likely be concentrated in the initial discharge portion of the batch. Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo.

Some firms have made the assumption that a residual contaminant would be worn off the equipment surface uniformly; this is also an invalid conclusion. Finally, the analytical power may be greatly reduced by dilution of the contaminate. Because of such problems, rinse and/or swab samples should be used in conjunction with the placebo method.

b. Detergent

If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected.

c. Test Until Clean

Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated since these retests actually document the presence of unacceptable residue and contaminants from an ineffective cleaning process.

VII. REFERENCES

1) J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisconsin's Control Procedures in Drug Production Seminar, July 17-22, 1966, William Blockstein, Editor, Published by the University of Wisconsin, L.O.C.#66-64234.

2) J.A. Constance, "Why Some Dust Control Exhaust Systems Don't Work," Pharm. Eng., January-February, 24-26 (1983).

3) S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5), 29-34 (1984)

4) W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng. 7(3), 29-33 (1987).

5) J.A. Smith, "A Modified Swabbing Technique for Validation of Detergent Residues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).

6) Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17(4), 54-60 (1993).

7) McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2nd Ed., edited by I.R. Berry and R.A. Nash, 319-349 (1993)

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Validation Guidelines for Pharmaceutical Dosage Forms

1.0 Scope

This Guidance document has been prepared to provide guidance to the pharmaceutical industry in dealing with validation issues for sterile and non-sterile dosage forms, biologicals, and radiopharmaceuticals. It should be noted that additional guidance related to sterile products and not contained in this document should also be considered. These requirements may be found in the five supplemental process validation guidelines available on the Inspectorate's website. The five documents pertain to the following specific processes:

• Moist Heat Sterilization for Pharmaceuticals
• Aseptic Processes for Pharmaceuticals
• Form-Fill-Seal for Pharmaceuticals
• Irradiation Sterilization for Pharmaceuticals
• Gaseous Sterilization for Pharmaceuticals

It is expected that importers and distributors of drug products have documented evidence that their vendors meet validation requirements.

2.0 Introduction

This document provides guidance on issues and topics related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms. These topics reflect an area in pharmaceutical, biological, and, radiopharmaceuticals manufacture that is noted as being important by both the Inspectorate and the pharmaceutical industry. These guidelines have been prepared to provide guidance to inspectors, evaluators and the industry in dealing with issues related to validation. Utilization of this information should facilitate compliance with Division 2, Part C of the Regulations to the Food and Drugs Act.

It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the Interpretation section for limits to be applied in defined circumstances, as well as the number of batches to be utilized for validation studies are for guidance purposes only. Inspectors, evaluators and the industry may consider other alternate means if proposed and documented with appropriate scientific justification.

3.0 Purpose

These guidelines outline the general principles that the Inspectorate considers to be acceptable elements of validation which may be used by fabricators, packagers/labellers for drug products. The Guidelines on Good Manufacturing Practices (GMP), Division 2, Part C of the Food and Drug Regulations require that:

• all critical production processes be validated
• validation studies are conducted in accordance with pre-defined protocols. Written reports summarizing recorded results and conclusions are prepared, evaluated, approved and maintained
• changes to production processes, operating parameters, equipment or materials that may affect product quality and/or the reproducibility of the process are also to be validated prior to implementation.

These guidelines are not intended to specify how validation is to be conducted, but are indicators of what is expected to be covered by fabricators, packagers/labellers.

The elements of validation presented in these guidelines are not intended to be all-encompassing. The particular requirements of validation may vary according to factors such as the nature of drug products eg. sterile, non-sterile, biologicals, and the complexity of the process. The concepts provided in these guidelines have general applicability and provide an acceptable framework for establishing a comprehensive approach to validation.

4.0 Definitions

Change Control (contrôle des changements): A written procedure that describes the action to be taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support system.

Cleaning Validation (validation des procédés de nettoyage): The documented act of demonstrating that cleaning procedures for the equipment used in fabricating/packaging will reduce to an acceptable level all residues (products/cleaning agents) and to demonstrate that routine cleaning and storage of equipment does not allow microbial proliferation.

Concurrent Validation (validation concomitante): A process where current production batches are used to monitor processing parameters. It gives assurance of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch.

Critical Process Parameter (paramètre critique du procédé): A parameter which if not controlled will contribute to the variability of the end product.

Equipment Qualification (qualification de l'équipement): Studies which establish with confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. The studies must include equipment specifications, installation qualification, and operational qualification of all major equipment to be used in the manufacture of commercial scale batches. Equipment Qualification should simulate actual production conditions, including "worst case"/ stressed conditions.

Installation Qualification (qualification d'installation): The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed.

Major Equipment (équipement principal): A piece of equipment which performs significant processing steps in the sequence of operations required for fabrication/packaging of drug products. Some examples of major equipment include tablet compression machines, mills, blenders, fluid bed dryers, heaters, drying ovens, tablet coaters, encapsulators, fermentors, centrifuges, etc.

Master Production Document (document-type de production): A document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula.

Measuring Devices (instruments de mesure): A device used in monitoring or measuring process parameters.

Operational Qualification (qualification opérationelle): The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications.

Process Capability (capacité du procédé): Studies conducted to identify the critical process parameters that yield a resultant quality, and their acceptable specification ranges, based on the established +/- 3 sigma deviations of the process, under stressed conditions but when free of any assignable causes.

Process Qualification (qualification du procédé): The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met.

Process Re-validation (revalidation du procédé): Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricators, major equipment or premises. Failure to meet product and process specifications in sequential batches would also require process re-validation.

Process Validation (validation du procédé): Establishing documented evidence with a high degree of assurance, that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Process validation may take the form of Prospective, Concurrent or Retrospective Validation and Process Qualification or Re-validation.

Prospective Validation (validation prospective): Conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant and may affect the product's characteristics. It is a pre-planned scientific approach and includes the initial stages of formulation development, process development, setting of process specifications, developing in-process tests, sampling plans, designing of batch records, defining raw material specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size batches, listing major process equipment and environmental controls.

Retrospective Validation (validation rétrospective): Conducted for a product already being marketed, and is based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which are now to be validated to conform to the requirements of Division 2, Part C of the Regulations to the Food and Drugs Act.

Validation (validation): The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment.

Validation Master Plan (plan maître de validation): An approved written plan of objectives and actions stating how and when a company will achieve compliance with the GMP requirements regarding validation.

Validation Protocol (protocole de validation): A written plan of actions stating how process validation will be conducted; it will specify who will conduct the various tasks and define testing parameters; sampling plans, testing methods and specifications; will specify product characteristics, and equipment to be used. It must specify the minimum number of batches to be used for validation studies; it must specify the acceptance criteria and who will sign/approve/ disapprove the conclusions derived from such a scientific study.

Validation Team (équipe de validation): A multi-disciplinary team of personnel primarily responsible for conducting and/or supervising validation studies. Such studies may be conducted by person(s) qualified by training and experience in a relevant discipline.

Worst Case Condition (condition de la pire éventualité): The highest and /or lowest value of a given parameter actually evaluated in the validation exercise.

5.0 Phases of Validation

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 SOPs have been followed, including Change Control procedures.

At this stage the Validation Team also assures that there have been no changes/ deviations that should have resulted in Requalification and Revalidation.

6.0 Interpretation

General Concepts:

Quality, safety and effectiveness must be built into the product. This requires careful attention to a number of factors such as the selection of quality materials/components, product and process design, control of processes, in-process control, and end-product testing.

Due to the complexity of the drug products, routine end-product testing alone is not sufficient due to several reasons. Furthermore, quality cannot be tested into the finished drug product but rather be built in the manufacturing processes and these processes should be controlled in order that the finished product meets all quality specifications. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications.

Validation protocol

A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested.

The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted.

In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented.

The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information:

• objectives, scope of coverage of the validation study
• validation team membership, their qualifications and responsibilities
• type of validation: prospective, concurrent, retrospective, re-validation
• number and selection of batches to be on the validation study
• a list of all equipment to be used; their normal and worst case operating parameters
• outcome of IQ, OQ for critical equipment
• requirements for calibration of all measuring devices
• critical process parameters and their respective tolerances
• description of the processing steps: copy of the master documents for the product
• sampling points, stages of sampling, methods of sampling, sampling plans
• statistical tools to be used in the analysis of data
• training requirements for the processing operators
• validated test methods to be used in in-process testing and for the finished product
• specifications for raw and packaging materials and test methods
• forms and charts to be used for documenting results
• format for presentation of results, documenting conclusions and for approval of study results.

Validation Master Plan

A validation master plan is a document that summarises the company's overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management.

Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorised standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results.

The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as re-validation.

The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP's and validation protocols and reports.

The format and content should include:

• introduction: validation policy, scope, location and schedule
• organizational structure: personnel responsibilities
• plant/ process /product description: rational for inclusions or exclusions and extent of validation
• specific process considerations that are critical and those requiring extra attention
• list of products/ processes/ systems to be validated, summarized in a matrix format, validation approach
• re-validation activities, actual status and future planning
• key acceptance criteria
• documentation format
• reference to the required SOP's
• time plans of each validation project and sub-project.

Installation and Operational Qualification

The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product. Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation that equipment, ancillary systems and sub-systems have been commissioned correctly. The end results are that all future operations will be reliable and within prescribed operating limits.

The basic principles are:

• equipment be correctly installed in accordance with an installation plan
• requirements for calibration, maintenance and cleaning be covered in approved SOP's
• tests be conducted to assure that equipment is operating correctly, under normal and "worst case" conditions
• operator training requirements pertaining to new equipment be conducted and documented.

At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications and acceptance criteria for test results. All these need to be reviewed, checked and authorised. It would be expected that representatives from the appropriate professional disciplines, eg. Engineering , Research and Development, Manufacturing, Quality Control and Quality Assurance be actively involved in these undertakings with the final authorisation given by a validation team or the Quality Assurance representative.

Installation Qualification (IQ):

I.Q. is the method of establishing with confidence that all major processing, packaging equipment and ancillary systems are in conformance with installation specifications, equipment manuals, schematics and engineering drawings. This stage of validation includes examination of equipment design, determination of calibration, maintenance and adjustment requirements.

For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a pre-delivery check of the equipment at the supplier's assembly facility. This pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the I.Q. stage, thus leading to a reduction in the scope of the I.Q. checks.

All equipment, gauges and services should be adequately identified and should be given a serial number or other reference number. This number should appear in the reports for the equipment validation studies conducted.

Installation qualification requires a formal and systematic check of all installed equipment against the equipment supplier's specifications and additional criteria identified by the user as part of the purchase specifications. These checks, tests and challenges should be repeated a significant number of times to assure reliable and meaningful results.

At the I.Q. stage the company should document preventive maintenance requirements for installed equipment. The preventive maintenance schedule should be incorporated into the routine maintenance schedule.

Note:

There will be cases where installation of the equipment had not been qualified at the time of installation, and the engineering drawings and manuals for the equipment are no longer available at the manufacturing site. However, the equipment in place operates for a lengthy period of time without any problem or modifications of its design since it was first installed. In such situations, the Inspectorate considers that it may be appropriate for those specific cases to verify a limited number of the most critical parameters demonstrating that the equipment had been adequately installed. Thereafter, the company could pass directly to the operational qualification (O.Q.) stage if there is sufficient documented evidence that these units have always been well maintained and calibrated according to an adequate pre-established schedule.

Operational Qualification (OQ):

The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment and systems should be identified at the O.Q. stage. The plans for the O.Q. should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met.

Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing and operating limits referred to as "worst-case" conditions. The completion of a successful O.Q. should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment.

The completion of satisfactory I.Q. and O.Q. exercises should permit a formal "release" of the equipment for the next stage in the process validation exercise as long as calibration, cleaning, preventive maintenance and operator training requirements have been finalised and documented.

Re-Qualification:

Modifications to, or relocation of equipment should follow satisfactory review and authorization of the documented change proposal through the change control procedure. This formal review should include consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventative maintenance program.

Process Validation:

It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate processes during routine production (Concurrent Validation). Processes which have been in use for some time without any significant changes may also be validated according to an approved protocol (Retrospective Validation).

a) Prospective Validation:

In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorised protocol.

All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined.

Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate these data.

Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation.

During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detailed testing should also be done on the final product in its package.

Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified.

Matrix or "Family" approaches to prospective process validation:

It may be possible and acceptable in particular circumstances for a manufacturer that uses the same process for several related products to develop a scientifically sound validation plan for that process rather than different plans for each product manufactured by that process.

The matrix approach generally means a plan to conduct process validation on different strengths of the same product, whereas the "family" approach means a plan to conduct process validation on different products manufactured with the same processes using the same equipment.

The validation process using these approaches must include batches of different strengths or products which should be selected to represent the worst case conditions or scenarios to demonstrate that the process is consistent for all strengths or products involved.

b) Concurrent Validation:

Unconditional use of this approach is not encouraged by the Inspectorate and is not acceptable as being the "norm". In using this approach there is always the risk of having to modify process parameters or specifications over a period of time. This situation often leads to questions regarding disposition of the batches that had already been released for sale, subsequently known to have undesired quality characteristics.

Concurrent validation may be the practical approach under certain circumstances. Examples of these may be:

• when a previously validated process is being transferred to a third party contract manufacturer or to another manufacturing site
• where the product is a different strength of a previously validated product with the same ratio of active / inactive ingredients
• when the number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control
• when the number of batches produced are limited (e.g. orphan drugs).

It is important in these cases however, that the systems and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process.

c) Retrospective Validation:

In many establishments, processes that are stable and in routine use have not undergone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated.

The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation.

Retrospective validation is only acceptable for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there have been recent changes in the formulation of the product, operating procedures, equipment and facility.

The source of data for retrospective validation should include amongst others, batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results.

For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. In such cases the study should be supplemented with data generated with concurrent or prospective validation.

Some of the essential elements for Retrospective Validation are:

• Batches manufactured for a defined period (minimum of 10 last consecutive batches)
• Number of lots released per year
• Batch size/strength/manufacturer/year/period
• Master manufacturing/packaging documents
• Current specifications for active materials/finished products
• List of process deviations, corrective actions and changes to manufacturing documents
• Data for stability testing for several batches
• Trend analyses including those for quality related complaints

Process Re-Validation:

Re-validation provides the evidence that changes in a process and /or the process environment that are introduced do not adversely affect process characteristics and product quality. Documentation requirements will be the same as for the initial validation of the process.

Periodic review and trend analysis should be carried out at scheduled intervals. Re-validation becomes necessary in certain situations. The following are examples of some of the planned or unplanned changes that may require re-validation:

• Changes in raw materials (physical properties such as density, viscosity, particle size distribution, and moisture, etc., that may affect the process or product).
• Changes in the source of active raw material manufacturer
• Changes in packaging material (primary container/closure system).
• Changes in the process (e.g., mixing time, drying temperatures and batch size)
• Changes in the equipment (e.g. addition of automatic detection system). Changes of equipment which involve the replacement of equipment on a "like for like" basis would not normally require a re-validation except that this new equipment must be qualified.
• Changes in the plant/facility.
• Variations revealed by trend analysis (e.g. process drifts)

A decision not to perform re-validation studies must be fully justified and documented.

Change Control:

Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations.

All changes must be formally requested, documented and accepted by the Validation Team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined.

Commitment of the company to control all changes to premises, supporting utilities, systems, materials, equipment and processes used in the fabrication/packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned.

The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation Team. The Team should decide if a re-validation must be conducted prior to implementing the proposed change.

7.0 References

1. Guidelines on General Principles of Process Validation, CDER, US-FDA 1987
2. Pharmaceutical Process Validation; 2^nd edition, Editors: I. R. Berry and R.A. Nash, 1993
3. Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation, PIC/S, August 2001

An Overview of Pharmaceutical Validation and Process Controls in Drug Development

Introduction
The development of a drug product is a
lengthy process involving drug discovery,
laboratory testing, animal studies, clinical
trials and regulatory registration. To further
enhance the effectiveness and safety of the
drug product after approval, many regulatory
agencies such as the United States Food
and Drug Administration (FDA) also require
that the drug product be tested for its
identity, strength, quality, purity and stability
before it can be released for use. For this
reason, pharmaceutical validation and
process controls are important in spite of the
problems that may be encountered1.
Process controls include raw materials
inspection, in-process controls and targets
for final product. The purpose is to monitor
the on-line and off-line performance of the
manufacturing process and then validate it.
Even after the manufacturing process is
validated, current good manufacturing
practice also requires that a well-written
procedure for process controls is established
to monitor its performance2.
This paper provides an overview of
pharmaceutical validation and process
controls in drug development. The validation
concept can be applied to new drugs, new
dosage forms and generic drug
development.
Essentials of Pharmaceutical Validation
Validation is an integral part of quality
assurance; it involves the systematic study
of systems, facilities and processes aimed at
determining whether they perform their
intended functions adequately and
consistently as specified. A validated
process is one which has been
demonstrated to provide a high degree of
assurance that uniform batches will be
produced that meet the required
specifications and has therefore been
formally approved. Validation in itself does
not improve processes but confirms that the
processes have been properly developed
and are under control3. Adequate validation
is beneficial to the manufacturer in many
ways3:
· It deepens the understanding of
processes; decreases the risk of
preventing problems and thus assures
the smooth running of the process.
· It decreases the risk of defect costs.
· It decreases the risk of regulatory noncompliance.
· A fully validated process may require
less in-process controls and endproduct
testing.
Validation should thus be considered in the
following situations:
· Totally new process;
· New equipment;
· Process and equipment which have
been altered to suit changing priorities;
and
· Process where the end-product test is
poor and an unreliable indicator of
product quality.
When any new manufacturing formula or
method of preparation is adopted, steps
should be taken to demonstrate its suitability
for routine processing. The defined process
should be shown to yield a product
consistent with the required quality. In this
phase, the extent to which deviations from
chosen parameters can influence product
quality should also be evaluated. When
certain processes or products have been
validated during the development stage, it is
not always necessary to revalidate the whole
process or product if similar equipment is
used or similar products have been
produced, provided that the final product
conforms to the in-process controls and final
product specification. There should be a
clear distinction between in-process control
and validation. In production, tests are
performed each time on a batch to batch
basis using specifications and methods
devised during the development phase. The
objective is to monitor the process
continuously4.
Major Phases in Validation
The activities relating to validation studies
may be classified into three:
Phase 1: This is the Pre-validation
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 and storage, and handling
of in-process and finished dosage forms,
equipment qualification, installation
qualification, master production document,
operational qualification and process
capacity.
Phase 2: This is the Process Validation
Phase. It is designed to verify that all
established limits of the critical process
parameter are valid and that satisfactory
products can be produced even under the
worst conditions.
Phase 3: Known as the Validation
Maintenance Phase, it requires frequent
review of all process related documents,
including validation of audit reports, to
assure that there have been no changes,
deviations, failures and modifications to the
production process and that all standard
operating procedures (SOPs), including
change control procedures, have been
followed. At this stage, the validation team
comprising of individuals representing all
major departments also assures that there
have been no changes/deviations that
should have resulted in requalification and
revalidation5. A careful design and validation
of systems and process controls can
establish a high degree of confidence that all
lots or batches produced will meet their
intended specifications. It is assumed that
throughout manufacturing and control,
operations are conducted in accordance with
the principle of good manufacturing practice
(GMP) both in general and in specific
reference to sterile product manufacture.
The validation steps recommended in GMP
guidelines can be summarized as follows5:
· As a pre-requisite, all studies should
be conducted in accordance with a
detailed, pre-established protocol or
series of protocols, which in turn is
subject to formal – change control
procedures;
· Both the personnel conducting the
studies and those running the process
being studied should be appropriately
trained and qualified and be suitable
and competent to perform the task
assigned to them;
· All data generated during the course of
studies should be formally reviewed
and certified as evaluated against
pre-determined criteria;
· Suitable testing facilities,
equipment, instruments and
methodology should be available;
· Suitable clean room facilities should
be available in both the ‘local’ and
background environment. There
should be assurance that the clean
room environment as specified is
secured through initial commissioning
(qualification) and subsequently
through the implementation of a
programme of re-testing – in-process
equipment should be properly
installed, qualified and maintained;
· When appropriate attention has been
paid to the above, the process, if
aseptic, may be validated by means of
“process simulation” studies;
· The process should be revalidated at
intervals; and
· Comprehensive documentation
should be available to define support
and record the overall validation
process.
Protocols should specify the following in
detail6:
· The objective and scope of study.
There should already be a definition of
purpose;
· A clear and precise definition of
process equipment system or subsystem,
which is to be the subject ofstudy with details of performance
characteristics;
· Installation and qualification
requirement for new equipment;
· Any upgrading requirement for existing
equipment with justification for the
change(s) and statement of
qualification requirement;
· Detailed stepwise statement of actions
to be taken in performing the study (or
studies);
· Assignment of responsibility for
performing the study;
· Statement on all test methodology to
be employed with a precise statement
of the test equipment and/or materials
to be used;
· Test equipment calibration requirements;
· References to any relevant standard
operating procedures (SOP);
· Requirement for the current format of
the report on the study;
· Acceptance criteria against which the
success (or otherwise) of the study is
to be evaluated; and
· The personnel responsible for
evaluating and certifying the acceptability
of each stage in the study and
for the final evaluation and certification
of the process as a whole, as
measured against the pre-defined
criteria.
All personnel involved in conducting the
studies should be properly trained and
qualified because they can, and often, have
a crucial effect on the quality of the endproduct.
All information or data generated as
a result of the study protocol should be
evaluated by qualified individuals against
protocol criteria and judged as meeting or
failing the requirements. Written evidence
supporting the evaluation and conclusion
should be available. If such an evaluation
shows that protocol criteria have not been
met, the study should be considered as
having failed to demonstrate acceptability
and the reasons should be investigated and
documented. Any failure to follow the
procedure as laid down in the protocol must
be considered as potentially compromising
the validity of the study itself and requires
critical evaluation of all the impact on the
study. The final certification of the validation
study should specify the pre-determined
acceptance criteria against which success or
failure was evaluated5.
Validation of Analytical Assays and Test
Methods
Method validation confirms that the analytical
procedure employed for a specific test is
suitable for its intended use. The validation
of an analytical method is the process by
which it is established by laboratory studies
that the performance characteristics of the
method meet the requirement for the
intended application. This implies that
validity of a method can be demonstrated
only though laboratory studies7. Methods
should be validated or revalidated8, 9:
· before their introduction and routine
use;
· whenever the conditions change for
which the method has been validated,
e.g., instrument with different
characteristics; and
· wherever the method is changed and
the change is outside the original
scope of the method.
Strategy for Validation of Methods
The validity of a specific method should be
demonstrated in laboratory experiments
using samples or standards that are similar
to the unknown samples analyzed in the
routine. The preparation and execution
should follow a validation protocol preferably
written in a step-by-step instruction format as
follows10:
· Develop a validation protocol or
operating procedure for the validation;
· Define the application purpose and
scope of the method;Define the performance parameters
and acceptance criteria;
· Define validation experiments;
· Verify relevant performance characteristics
of the equipment;
· Select quality materials, e.g.,
standards and reagents;
· Perform pre-validation experiments;
· Adjust method parameters and/or
acceptance criteria, if necessary;
· Perform full internal (and external)
validation experiments;
· Develop SOPs for executing the
method routinely;
· Define criteria for revalidation;
· Define type and frequency of system
suitability tests and/or analytical quality
control (AQC) checks for the routine;
and
· Document validation experiments and
results in the validation report.
Environmental Considerations: Cleaning
and Clean Room Standards
Cleaning validation is documented proof that
one can consistently and effectively clean a
system or equipment items. The procedure
is necessary for the following reasons11, 12:
· It is a customer requirement – it
ensures the safety and purity of the
product;
· It is a regulatory requirement in active
pharmaceutical product manufacture;
and
· It also assures from an internal control
and compliance point of view the
quality of the process.
The FDA guide to inspections13 intended to
cover equipment cleaning (chemical
residues only) expects firms to have written
procedure (SOPs) detailing the cleaning
processes and also written general
procedure on how cleaning processes will be
validated. FDA expects a final validation
report which is approved by management
and which states whether or not the cleaning
process is valid. The data should support a
conclusion that residues have been reduced
to an “acceptable level”14. Harder14 cited five
crucial elements:
1. A standard operating procedure (SOP)
for cleaning with a checklist;
2. A procedure for determining cleanliness
(rinse or swab);
3. An assay for testing residual drug
levels;
4. Pre-set criteria for testing chemical
and microbial limit to which to
equipment must be cleaned; and
5. Protocol for cleaning validation.
Harder14 recommended that the procedure
be tested for, requiring it to be successful on
three successive cleanings and there should
be periodic revalidation as well as
revalidation after significant changes.
Jenkins and Vanderwielen15 presented an
overview of cleaning validation covering
strategy and determination of residue limits,
method of sampling and analysis noting that
“increased use of multi-purpose equipment”
has produced increased interest in cleaning
validation. The cleaning protocol must be
thorough and must be checked. Training is
essential. A validation program requires
· criteria for acceptance after cleaning,
· appropriate methods of sampling,
· a maximum limit set for residues, and
· test methods that must themselves be
tested.
Products to be tested may be put into groups
rather than testing all of them16. The most
important may not be the highest volume
product but those capable of causing the
largest possible problems if contaminated or
if they contaminate the products (solubility of
the drug is an important issue). Equipment
may also be tested in groups.
Process Validation
Process validation is the means of ensuring
and providing documentary evidence that
processes (within their specified designparameters) are capable of repeatedly and
reliably producing a finished product of the
required quality5. It would normally be
expected that process validation be
completed prior to the release of the finished
product for sale (prospective validation).
Where this is not possible, it may be
necessary to validate processes during
routine production (concurrent validation).
Processes, which have been in use for some
time without any significant changes, may
also be validated according to an approved
protocol (retrospective validation)10-17.
Pre-requisites for Process Validation
Before process validation can be started,
manufacturing equipment and control
instruments as well as the formulation must
be qualified. The information on a
pharmaceutical product should be studied in
detail and qualified at the development
stage, i.e., before an application for
marketing authorization is submitted. This
involves studies on the compatibility of active
ingredients and recipients, and of final drug
product and packaging materials, stability
studies, etc. Other aspects of manufacture
must be validated including critical services
(water, air, nitrogen, power supply, etc.) and
supporting operations such as equipment
cleaning and sanitation of premises. Proper
training and motivation of personnel are prerequisites
to successful validation18-20.
The Pharmaceutical Process Equipment
The key idea of validation is to provide a
high level of documented evidence that the
equipment and the process conform to a
written standard. The level (or depth) is
dictated by the complexity of the system or
equipment. The validation package must
provide the necessary information and test
procedures required to provide that the
system and process meet specified
requirements21. Validation of pharmaceutical
process equipment involves the following10:
· Installation Qualification: This
ensures that all major processing and
packaging equipment, and ancillary
systems are in conformity with
installation specification, equipment
manuals schematics and engineering
drawing. It verifies that the equipment
has been installed in accordance with
manufacturers recommendation in a
proper manner and placed in an
environment suitable for its intended
purpose.
· Operational Qualification: This is
done to provide a high degree of
assurance that the equipment
functions as intended. Operational
qualification should be conducted in
two stages:
· Component Operational Qualification,
of which calibration can
be considered a large part.
· System Operational Qualification
to determine if the entire
system operates as an integrated
whole.
· Process Performance Qualification:
This verifies that the
system is repeatable and is
consistently producing a quality
product14.
These exercises assure, through appropriate
performance lists and related documentation,
that equipment, ancillary systems and
sub-systems have been commissioned
correctly. The end results are that all future
operations will be reliable and within
prescribed operational limits.
At various stages in a validation exercise
there are needs for protocols, documentation,
procedures, specifications and
acceptance criteria for test results. All these
need to be reviewed, checked and
authorized. It would be expected that
representatives from the professional
disciplines, e.g., engineering, research and
development, manufacturing, quality control
and quality assurance are actively involved
in these undertakings with the final
authorization given by a validation team or
the quality assurance representative22.Approaches to Validation Process
There are two basic approaches to the
validation of the process itself (apart from the
qualification of equipment used in
production, the calibration of control and
measurement instruments, the evaluation of
environmental factors, etc). These are the
experimental approach and the approach
based on the analysis of historical data. The
experimental approach, which is applicable
to both prospective and concurrent
validation, may involve23
· extensive product testing,
· simulation process trials,
· challenge/worst case trials, and
· control of process parameters (mostly
physical).
One of the most practical forms of process
validation, mainly for non-sterile products, is
the final testing of the product to the extent
greater than that required in routine quality
control. It may involve extensive sampling,
far beyond that called for in routine quality
control and specifications, and often for
certain parameters only. Thus, for instance,
several hundred tablets per batch may be
weighed to determine unit dose uniformity.
The results are then treated statistically to
verify the normality of the distribution and to
determine the standard deviation from the
average weight. Confidence limits for
individual results and for batch homogeneity
are also estimated. Strong assurance is
provided that samples taken at random will
meet regulatory requirements if the
confidence limits are within compendial
specifications24.
In the approach based on analysis of
historical data, no experiments are
performed in retrospective validation, but
instead all available historical data
concerning a number of batches are
combined and jointly analysed, if production
is proceeding smoothly during the period
preceding validation and the data in
process inspection and final testing of the
product are combined and treated
statistically. The results including the
outcome of process capability studies, trend
analysis, etc., will indicate whether the
process is under control or not.
Expert Evaluation
This is an evaluation of the entire study
against the protocol requirements as outlined
above. It should be prepared and the
conclusion drawn at each stage stated. The
final conclusions should reflect whether the
protocol requirements were met. The
evaluation should include an assessment of
the planned calibration and maintenance
programmes for the equipment and
instrumentation to maintain the validated
conditions. In addition, all process monitoring
and control procedures required to routinely
ensure that the validated conditions are
maintained should be reported. The
evaluation should be signed by authorized
officers of the organization who were
members of the team establishing the
protocol and who have appropriate expertise
in the area assigned to them. Overall
approval of the study should be authorized
by the head of the validation team and the
head of the quality control department21.
The Validation Report
A written report should be available after
completion of the validation. If found
acceptable, it should be approved and
authorized (signed and dated). The report
should include at least the following4:
· Title and objective of study;
· Reference to protocol;
· Details of material;
· Equipment;
· Programmes and cycles used;
· Details of procedures and test
methods;
· Results (compared with acceptance
criteria); and
· Recommendations on the limit and
criteria to be applied on future basis.Conclusion
It is necessary, before approval of a new
drug, that an accurate and reliable
assessment for its effectiveness and safety
for the intended indication and target patient
population is demonstrated. Pharmaceutical
validation which includes assay validation,
cleaning validation, equipment validation as
well as the overall process validation is
crucial in stability analysis, animal studies
and early phases of clinical development
such as bioavailability/bioequivalence
studies. After the drug is approved,
pharmaceutical validation and process
control are necessary to ensure that the drug
product will meet/set pharmaceutical
standards for identity, strength, quality,
purity, stability, evaluation safety and
efficacy.
In general, pharmaceutical validation and
process control provide a certain assurance
of batch uniformity and integrity of the
product manufactured.
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823. Geneva: WHO, 1992: pp 14-96.

cleaning validation Summary

A validation policy should be written for a plant including cleaning validation.
An cleaning validation program should contain the following elements:
1. Assess equipment and products (previous, following)
2. Assess impact of this process on routine processes. If covered under bracketing
then no further validation is required.
3. Determine an appropriate cleaning agent and method
4. Determine acceptance criteria for the residue(s) (including cleaning agents).
5. Determine degree of evaluation required to validate the procedure.
6. Decide what residue(s) (including cleaning agents), are to be tested for based on
solubilities, toxicities etc. and document rational behind decision.
7. Develop sampling and analytical methods for recovery and detection of residues
(swab/rinse, HPLC/dry residue etc.)
8. Acceptance Criteria for the Validation
9. Compile and approve Validation protocol
10. Perform Validation Studies in accordance with protocol
11. Compile and approve a Validation report documenting studies, conclusions and
recommendations.
12. Revalidation policy

Cleaning Validation Minimum requirements

If company policy is not to validate all equipment cleaning procedures for all products
then as a minimum requirement the validation policy should encompass conditions
which represent the most appropriate challenges (worst case) to the procedure.
These would include, as an example, such things as:
· Removal of products which contain the products with the greatest biological
activity.
· Removal of products containing the products/intermediates/byproducts with the
least solubility.
These represent studies that are minimally required as part of a validation, the results
from which could be used to support lesser challenges to the procedure. It is often
termed product grouping.
· The maximum idle time before cleaning.
A validation program generally encompasses three consecutive successful replicates to
establish that the procedure is reproducibly effective although companies should
evaluate each situation individually.
Where equipment of similar size, design and construction is cleaned by the same
procedure, studies need not be conducted on each unit, as long as a total of three
successful replicates are done on similar pieces of equipment (equipment grouping).
Concurrent Validation may be appropriate when product is manufactured infrequently.

Cleaning Validation reports

A validation report is necessary to present the results and conclusions and
secure approval of the study. The report should include the following:
· Summary of or reference to the procedures used to clean, sample and test
· Physical and analytical test results or references for same, as well as any
pertinent observations
· Conclusions regarding the acceptability of the results, and the status of
the procedure(s) being validated
· Any recommendations based on the results or relevant information
obtained during the study including revalidation practices if applicable.
· Approval of conclusions
· Review any deviations for the protocol that occurred.
· In cases where it is unlikely that further batches of the product will be
manufactured for a period of time it is advisable to generate interim
reports on a batch by batch basis until such time as the cleaning validation
study has been completed. (Typically, in Active Pharmaceutical
Ingredient Pharmaceutical manufacture, verification is deemed
appropriate during development of the cleaning methods. Where
products are manufactured infrequently, verification may be applied over
a period of time until all measuring data has been collected for the
Validation Report.)
· The report should conclude an appropriate level of verification
subsequent to validation.

Validation protocols Cleaning

A Validation Protocol is necessary to define the specific items and activities
that will constitute a cleaning validation study. It is advisable for companies to
have drawn up a Master Validation plan indicating the overall Cleaning
Validation strategy for either the product range / equipment type / entire site.
The protocol must be prepared prior to the initiation of the study and must
either include or reference the documentation required to provide the following
information:
· The objective of the study:
What cleaning process is to be validated (indicating the product to be
removed and the equipment from which it is to be removed)?
If this study is to be employed to demonstrate the acceptability of the
cleaning procedure for a group of products the rational for doing so
should also be detailed here.
The cleaning procedure(s) to be validated should be identified i.e.
cleaning agents, soakage times, equipment parameters, number of
cleaning cycles etc.
· Scope of the study:
The company must evaluate the process and determine which residues are
to be tested for and which are not to be based on sound scientific
rational.
What residues (including cleaning agents) are to be tested for, why those
residues (if more residues may be present than are being tested for all
residues should be under control see comments at 8.4). How many times
should the study be run before a report is compiled and recommendations
made.
· Listing of the process parameters to be verified
This is particularly necessary when automated or semi-automated
cleaning techniques are to be employed.
· Sampling and inspection procedure to be used.
The types of sampling methods to be used, where the samples are to be
removed from and how many samples are to be taken. Any particular
requirements should also be stated i.e. for sterile sampling / sampling
light sensitive products.
An equipment sampling diagram should be referenced.
· Personnel responsibilities during the study

Analytical methods Cleaning Validation

In order for the analytical testing of the cleaning validation samples (swabs or
rinses) to yield meaningful results, the analytical methods used should be
validated. This should be documented.
The basic requirements are:
· The ability to detect the target substance(s) at levels consistent with the
acceptance criteria
· The ability to detect the target substance(s) in the presence of other
materials that may also be present in the sample (selectivity)
(Companies might want to consider the following:
Where more than one impurity is suspected (which is probably the normal
case in API manufacturing) a method could be proposed that is not
necessarily specific for each of the impurities but detects them all
together. Then additionally the assumption must be made, that the worst
case (e.g. most active) impurity represents the whole residue. This is
secure approach for the patients and could be accepted by the authorities.
It is also an practicable approach for the industry because such methods
are for example dry residue determination for non volatile impurities or
TOC determination for water rinses, which are very simple methods. )
· The analytical method should include a calculation to convert the amount
of residue detected in the sample to 100% if the recovery data generated
indicates a recovery outside of an allowed range.
· Stability of samples over time if the time interval between removal and
testing of samples potentially effects sample integrity.

Sampling Cleaning Validation

In developing the sampling plan for a validation study, it makes scientific sense
to
incorporate an understanding of the acceptance criteria and the limitations of the
sampling method relative to the surface to be sampled.
The two methods of sampling generally employed are swab and / or rinse
sampling. (If neither or these methods is shown be a scientifically sound method
for testing in a specific instance then an alternative is to consider testing the next
product.)
The selection of either of these techniques must be consistent with sound
scientific judgment and must support the objective of the study, which is to
demonstrate that the amount of residual material in the equipment has been
reduced to acceptable levels.
Each method is described in brief below.
1. SWAB:
· Swab sampling does not cover the entire equipment surface area therefore
sites must be chosen with care. It is important that, as a minimum, the
swab sites represent worst case locations on the equipment and that the
result is then extrapolated to account for the total product contact surface
area. This calculation makes it possible to make a worst case determination
of potential carryover into subsequent product.
· Due to the nature of this method which employs physical forces as well as
chemical forces it may be necessary to perform sampling technique
evaluation.
· Swabbing efficiency (% recovery) for the swabbing method must be
determined.
· It is necessary to ensure that extractables of the swab do not interfere with
the sampling method.
· Using this technique it is possible to sample insoluble residues due to the
physical action associated it.
2. RINSE:
· The solvent rinse occurs after cleaning has been completed
· This method is not as direct as swabbing but will cover the entire surface
area (and parts inaccessible to swabs)
· It is important to ensure chosen solvent has appropriate recovery for
residues being quantified
· This method allows much greater ease of sampling than swabbing
· A reduced no of samples are required to generate a carryover figure.
(Other sampling methods which may be employed in addition to swab / rinse
sampling during a validation may include: placebo sampling, testing subsequent
batches for residues, use of coupons (test pieces), etc. )

Cleaning procedures

Written cleaning procedures for each piece of equipment and process1 must be
prepared. It is vital that the equipment design is evaluated in detail in
conjunction with the product residues to be removed, the available cleaning
agents and cleaning techniques when determining the optimum cleaning
procedure for the equipment.
Cleaning procedures should be sufficiently detailed to remove the possibility of
any inconsistencies during the cleaning process.
A. Equipment parameters to be evaluated
· Identification of the equipment to be cleaned
· Difficult to clean areas
· Property of materials
· Ease of disassembly
· Fixed or not
· Etc.
B. Residues to be cleaned
· Cleaning limits
· Solubility's of the residues
· Length of campaigns
· Etc.
C. Cleaning agent parameters to be evaluated
· Preferably materials that are normally used in the process
· Detergents available (as a general guide, minimize use of detergents unless
absolutely required)
· Solubility properties
· Environmental considerations.
· Health and safety considerations
· Etc.
D. Cleaning techniques to be evaluated
· Manual cleaning
· CIP (Clean-in place)
· COP (clean-out-of-place)
· Semi automatic
· Automatic
· Time considerations
· Number of cleaning cycles
· Etc.
E. Other requirements
Procedures must be determined to be operator independent i.e. rugged and
reproducible, during the validation studies.
The Cleaning documentation should include the following items in order to ensure that
it can be followed reproducibly and maintained subsequent to Validation.
· Detailed definition of levels of cleaning to be performed.
· Detailed description of cleaning methods.
· The necessity to inspect and verify equipment cleanliness prior to manufacture of
next batch should be stated in the SOP and recorded on the batch record.
· The SOP should detail where verification of cycle parameters (if automated) and
checklists (for complex manual procedures) is necessary.
· Where microbial contamination may be an issue, consideration should be given to
the integrity of the vessel prior to manufacture.
Written cleaning procedures may also include additional items not specified above,
these would include, as an example, the steps needed to protect the equipment from
contamination after cleaning.