Validating Processes For Surface Preparation

Validation of processes for surface preparation is crucial to many industries, including pharmaceuticals, biomedical device and even food preparation. The effectiveness of the methods for surface preparation in these industries should be established, documented and monitored on an on-going basis.
Validation helps ensure that the surface has been cleaned to an acceptable contamination level. This maximum tolerable contamination level may be termed the target level. Sampling and analysis techniques must have the specificity, sensitivity, reliability and robustness to assure that contamination does not exceed the target limit. The areas of surface where contamination is most adherent or where the negative consequences of contamination are greatest must receive special attention. The nature of potential contaminants must also be considered. While much attention is paid to biological debris, microbes, and pyrogens, other organic and inorganic contaminants can potentially impact product quality.
As applied to processes for surface preparation, validation is a quantifiable, structured approach to demonstrate and document process effectiveness and process consistency. The following are suggestions for a comprehensive validation process.
Process efficacy must be evaluated prior to implementing the procedure. The procedure should require re-validation after changes to the processes that may significantly affect the types and amount of contamination left on the surface, or when significant changes are made to the cleaning process and result of re-validation must be documented.
The essence of process validation is documented, scientific proof of consistent successful process performance. Full, detailed documentation is an integral part of the validation process to show that the process consistently performs as expected and yields a result that consistently meets predetermined specifications. Predetermined specifications in this situation refer to the maximum acceptable level of contamination that can be tolerated on the surface. Written procedures must be established detailing the surface preparation processes. Those responsible for performing, approving and documenting the validation study and the acceptance criteria must be included, as should documentation of the frequency of process monitoring. Written procedures on how process changes will be validated and requirements for documentation of validation should also be developed.
Sampling and analysis methods must provide for sample collection and detection of levels of contamination relevant to the target limit. The technique must be suited to the types and the target level of contamination. The detection technique should be reviewed periodically for its effectiveness and relevance to the type and level of contaminants currently encountered. Prior to accepting and implementing a validation procedure, the analytical or surface testing technique itself should be evaluated and successfully replicated at least three times. Where possible, direct surface monitoring is desirable and may be preferred over indirect, extractive methods. Part configuration and test method sensitivity must be considered.
Establishing appropriate target levels of maximum acceptable contamination is a challenge. Generally, the main consideration should be as to how much surface contamination can be tolerated. There are many ways of establishing contamination limits. Cost must be considered in determining the target contamination level. For each level of surface contamination there is an associated cost of achieving that level. In addition, with each level of contamination there is a level of non-conformance or failures. The cost associated with each level of non-conformance must also be considered. The maximum acceptable level (Target Level) is the one where the incremental cost of removing more contamination is not offset by the corresponding reduction in the non-conformance or failure cost. If, however, the cost of non-conformance is a health threatening, or life threatening product failure, then the target contamination level must be adjusted to an appropriately low level.The situation is akin to extrapolating from animal studies to humans using the lowest dose of a drug or chemical at which no adverse effects are seen.The appropriate “safety factor” or risk factor will depend on the nature of the observed problem animals or the anticipated consequence in humans.
Some general considerations in establishing target levels include the effect of different levels of contamination on the success of subsequent operations; the detection capability of the various analytical techniques available; the anticipated end-use and performance requirement of the product; and the economic and social cost of non-conformance or failure.

Process Validation

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INTRODUCTION

The Quality System (QS) regulation defines process validation as establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications [820.3(z)(1)]. The requirement for process validation appears in section 820.75 of the Quality System (QS) regulation. The goal of a quality system is to consistently produce products that are fit for their intended use. Process validation is a key element in assuring that these principles and goals are met.

The process validation requirements stated in the QS regulation and the guidance offered here have general applicability to manufacturing processes for medical devices. Many technologies are used in the production of medical devices. The details of process validation will vary according to the nature of the medical device (e.g., sterile or non-sterile) and the nature and complexity of the process being validated.

Processes are developed according to the design controls in 820.30 and validated according to 820.75. The process specifications, hereafter called parameters, are derived from the specifications for the device, component or other entity to be produced by the process. The parameters are documented in the device master record per 820.30, 820.40 and 820.181. The process is developed such that the required parameters are achieved. To ensure that the output of the process will consistently meet the required parameters during routine production, the process is validated.

The basic principles for validation may be stated as follows:

• Establish that the process equipment has the capability of operating within required parameters;

• Demonstrate that controlling, monitoring, and/or measuring equipment and instrumentation are capable of operating within the parameters prescribed for the process equipment;

• Perform replicate cycles (runs) representing the required operational range of the equipment to demonstrate that the processes have been operated within the prescribed parameters for the process and that the output or product consistently meets predetermined specifications for quality and function; and

• Monitor the validated process during routine operation. As needed, requalify and recertify the equipment.

TERMS AND DEFINITIONS

Terms other than those used herein may be found in the literature.

Validation: confirmation by examination and provision of objective evidence that the particular requirement for a specific intended use can be consistently fulfilled.

Process validation: establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.

Installation qualification: establishing documented evidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

Process performance qualification: establishing documented evidence that the process is effective and reproducible.

Product performance qualification: establishing documented evidence through appropriate testing that the finished product produced by a specified process(es) meets all release requirements for functionality and safety.

Prospective validation: validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

Retrospective validation: validation of a process for a product already in distribution based upon accumulated production, testing and control data.

Validation protocol: a written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.

WHY VALIDATE PROCESSES

There are many reasons, in addition to the regulatory requirements, for validating processes. A manufacturer can assure through careful design of the device and packaging, careful design and validation of processes, and process controls, that there is a high probability that all manufactured units will meet specifications and have uniform quality. The dependence on intensive in-process and finished device testing can be reduced. However, in-process and finished product testing still play an important role in assuring that products meet specifications. A properly validated and controlled process will yield little scrap or rework, resulting in increased output. Consistent conformance to specifications is likely to result in fewer complaints and recalls. Also, when needed, the validation files contain data to support improvements in the process or the development of the next generation of the process.

WHAT PROCESSES SHOULD BE VALIDATED

Where process results cannot be fully verified during routine production by inspection and test, the process must be validated according to established procedures [820.75(a)]. When any of the conditions listed below exist, process validation is the only practical means for assuring that processes will consistently produce devices that meet their predetermined specifications:

• Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished devices;

• Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product.¹

• Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished devices.² [RETURN from footnotes]

• The process capability is unknown, or it is suspected that the process is barely capable of meeting the device specifications.

TYPES OF PROCESS VALIDATION

Process validation may be conducted at different points during the life cycle of a product. The types of process validation are defined in terms of when they occur in relation to product design, transfer to production and release of the product for distribution.

Prospective Validation

Prospective validation is conducted before a new product is released for distribution or, where the revisions may affect the product's characteristics, before a product made under a revised manufacturing process is released for distribution.

Concurrent validation is a subset of prospective validation and is conducted with the intention of ultimately distributing product manufactured during the validation study. Concurrent validation is feasible when nondestructive testing is adequate to verify that products meet predetermined specifications and quality attributes. If concurrent validation is being conducted as the initial validation of a new process or a process which has been modified, product should be withheld from distribution until all data and results of the validation study have been reviewed, and it has been determined that the process has been adequately validated.

Concurrent validation may be conducted on a previously validated process to confirm that the process is validated. If there have been no changes to the process and no indications that the process is not operating in a state of control, product could be released for distribution before revalidation of the process is completed. There is some risk to early release of product in that subsequent analysis of data may show that the process is not validated.

Retrospective Validation

Retrospective validation is the validation of a process based on accumulated historical production, testing, control, and other information for a product already in production and distribution. This type of validation makes use of historical data and information which may be found in batch records, production log books, lot records, control charts, test and inspection results, customer complaints or lack of complaints, field failure reports, service reports, and audit reports. Historical data must contain enough information to provide an in-depth picture of how the process has been operating and whether the product has consistently met its specifications. Retrospective validation may not be feasible if all the appropriate data was not collected, or appropriate data was not collected in a manner which allows adequate analysis.

Incomplete information mitigates against conducting a successful retrospective validation. Some examples of incomplete information are:

• Customer complaints which have not been fully investigated to determine the cause of the problem, including the identification of complaints that are due to process failures;

• Complaints were investigated but corrective action was not taken;

• Scrap and rework decisions that are not recorded, investigated and/or explained;

• Excessive rework;

• Records that do not show the degree of process variability and/or whether process variability is within the range of variation that is normal for that process, for example, recording test results as "pass" or "fail" instead of recording actual readings or measurements results in the loss of important data on process variability; and

• Gaps in batch records for which there are no explanations. (Retrospective validation cannot be initiated until the gaps in records can be filled or explained.)

If historical data is determined to be adequate and representative, an analysis can be conducted to determine whether the process has been operating in a state of control and has consistently produced product which meets its predetermined specifications and quality attributes. The analysis must be documented.

After a validated process has been operating for some time, retrospective validation can be successfully used to confirm continued validation of that process if no significant changes have been made to the process, components, or raw materials.

Statistical process control is a valuable tool for generating the type of data needed for retrospective analysis to revalidate a process and show that it continues to operate in a state of control.

PROCESS VALIDATION STUDIES

Planning the Process Validation Study

Careful planning of a validation study is essential to ensure that the process is adequately validated. The plan should include design reviews. The plan for the validation study is documented in the validation protocol. A copy of the protocol and validation results are placed in the Design History File (DHF) [820.30 (j)] or quality system record file (820.186). The operational, monitoring, and other production-related procedures are part of the device master record (DMR) (820.181). Planning for the validation should include the following elements as well as any other relevant issues that must be addressed to conduct the validation study:

• identification of the process to be validated;

• identification of device(s) to be manufactured using this process;

• criteria for a successful study;

• length and duration of the study;

• assumptions (shifts, operators, equipment, components);

• identification of equipment to be used in the process [820.75(b)(2)];

• identification of utilities for the process equipment and quality of the utilities;

• identification of operators and required operator qualifications [820.75(b)(2)];

• complete description of the process {may reference the DMR [820.181(b)]};

• relevant specifications including those for the product, components, manufacturing materials, the environment, etc. [may reference the DMR and quality system files {820.181(a) and (b); 820.186};

• any special controls or conditions to be placed on preceding processes during the validation;

• process parameters to be controlled and monitored, and methods for controlling and monitoring [820.70(a); 820.75(b)(2)];

• product characteristics to be monitored and method for monitoring [820.70(a)(2); 820.75(b)(2); 820.80(c)];

• any subjective criteria used to evaluate the product;

• definition of what constitutes nonconformance for both measurable and subjective criteria;

• statistical methods for data collection and analysis (820.250);

• consideration of maintenance and repairs [820.72(a)];

• conditions that may indicate that the process should be revalidated [820.75(c)];

• stages of the study where design review is required; and

• approval(s) of the protocol.

The validation plan should also cover the installation and operation qualification of any equipment used in the process, process performance qualification, and product performance qualification.

Installation and Operation Qualification

After process equipment is designed or selected, it should be installed, reviewed, calibrated, challenged, and evaluated to ensure that it is capable of operating within established limits and tolerances as well as throughout all anticipated operating ranges. Installation and operation qualification studies establish confidence that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use [820.70(g)].

The installation and operation qualification phases of process validation include:

• examining equipment design and supplied documentation;

• determining installation requirements;

• establishing any needed environmental controls and procedures;

• assuring that the work area has sufficient space to perform the processing and associated activities;

• installing the equipment;

• verifying correct installation;

• establishing manufacturing procedures for the monitoring, operation, and control of the equipment including the minimum number of operators;

• determining calibration, cleaning, maintenance, adjustment, and expected repair requirements;

• identifying important elements of the equipment that could affect the output or finished device;

• verifying that the system or subsystem performs as intended throughout all anticipated operating ranges; and

• documenting the above information.

Equipment fabricators may perform qualification runs at their facilities and analyze the results to determine that the process equipment is ready for delivery to the medical device manufacturer. Device manufacturers should obtain copies of the suppliers' qualifications studies to use as guides, to obtain basic data, and to supplement their own qualification studies. However, it is usually insufficient to rely solely upon the representations and studies of the equipment supplier. The device manufacturer is ultimately responsible for evaluating, challenging, and testing the equipment and deciding whether the equipment is suitable for use in the manufacture of a specific device(s). The evaluations may result in changes to the equipment or process. Such changes must meet QS requirements in 820.30, Design Control; 820.40, Document Controls; 820.50, Purchasing Controls; 820.70, Process Controls; 820.72, Inspection, Measuring, and Test Equipment; 820.75, Process Validation; 820.181, Device Master Record.

Installation and operation qualifications should include establishing pertinent methods, procedures, and schedules for calibration, cleaning, and maintenance, and establishing a repair parts list for each piece of equipment. Planning for eventual maintenance and repairs can reduce or prevent confusion during emergency repairs which could lead to improper repairs such as the use of the wrong replacement part. Post-repair cleaning, calibration, and re-start requirements should be established if necessary to prevent inadvertent manufacture of nonconforming devices. The objective is to assure that all repairs can be performed in a way that will not affect the characteristics of material processed or devices manufactured after repairs.

Process and monitoring equipment (instruments) should be calibrated at the beginning of the validation study, and the calibration should be checked at the end of the study to establish confidence in the validation of the process. Equipment found out of calibration at the end of a process validation study may indicate that the process has not been operating in a state of control and cannot be considered validated. More frequent calibration or more robust equipment may be necessary, or you may wish to use stand-alone instruments in parallel with the built-in process monitoring equipment.

It is important to document installation and operation qualification studies. Such documentation can substitute for part of the requalification of equipment in future process validation studies. When equipment is moved to a new location, installation and operation should be requalified. By comparing data from the original installation and operation qualification and the requalification, the manufacturer can determine whether there have been any changes in equipment performance as a result of the move. Changes in equipment performance should be evaluated to determine whether it is necessary to revalidate the process.

Process Performance Qualification

The purpose of process performance qualification is to rigorously test the process to determine whether it is capable of consistently producing an output or in-process or finished devices which meet specifications. In entering theprocess performance qualification phase of validation, it is understood that the:

• device, packaging, and process specifications have been established, documented, and essentially proven acceptable through engineering, laboratory or other verification methods [820.30; 820.70(a)]; and

• process and ancillary equipment and the environment have been judged acceptable on the basis of installation and operation qualification studies [820.70(g)].

Challenges to the process should simulate conditions that will be encountered during actual production. Challenges should include the range of conditions allowed in written standard operating procedures and should be repeated enough times to assure that the results are meaningful and consistent. Challenges may need to include forcing the preceding process to operate at its allowed upper and lower limits.

Process and product data should be analyzed to determine what the normal range of variation is for the process output. Knowing what is the normal variation of the output is crucial in determining whether a process is operating in a state of control and is capable of consistently producing the specified output.

Process and product data should also be analyzed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include:

• temperature,
• humidity,
• variations in electrical supply,
• vibration,
• environmental contaminants,
• purity of process water,
• light, and
• inadequate employee training.

Appropriate measures should be taken to eliminate controllable causes of variation. For example, extreme variations in temperature can be eliminated by installing heating and air conditioning. Employee training can be improved and conducted more frequently, and employees can be monitored more closely to assure that they are properly performing the process. Eliminating controllable causes of variation will reduce variation in the process output and result in a higher degree of assurance that the output will consistently meet specifications.
After routine production begins, data derived from monitoring the process and output product can be analyzed for variation and compared to the normal range of variation. Such analyses can detect when the process output is shifting so that corrections can be made before, or soon after, nonconforming product is produced.

Product Performance Qualification

The purpose of product performance qualification is to demonstrate that the process has not adversely affected the finished product and that the product meets its predetermined specifications and quality attributes. Product performance qualification and design validation of initial finished devices are closely related. According to the design control requirements, design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents [820.30(g)]. Products used for design validation should be manufactured using the same production equipment, methods and procedures that will be used in routine production. Otherwise, the product used for design validation may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets pre-determined specifications and quality attributes.

Design validation can be conducted using finished products made during process validation studies and will satisfy the need for product performance qualification. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing production units under actual or simulated use conditions [820.30(g)]. Original designs and design changes are subject to design control requirements [820.30(i)]. The results of design validation are subject to review under the design control review requirements [820.30(e)].

DOCUMENTATION

The requirements for process validation are described in section 820.75 and include documentation requirements for the process validation study phase as well as for routine production using a validated process. Records of validation activities and results must be maintained [820.75(a)]. Validation protocols and results may be filed in the DHF [820.30(j)] or in the QS files (820.186). Records must include the date and signature of the individual(s) approving the validation and, where appropriate, the major equipment validated [820.75(a)]. Procedures for monitoring and control of process parameters must be established and maintained for validated processes [820.75(b)]. Procedures for the operation, monitoring and control of processes are part of the DMR (820.181).

When a validated process is used for manufacturing finished devices, the process must be performed by a qualified individual [820.75(b)(1)]. Records must be maintained of the monitoring and control methods and data; where appropriate, the individual(s) performing the process; the date performed; and major equipment used. The records should be maintained in the DHR (820.184).

REVALIDATION

As long as the process operates in a state of control and no changes have been made to the process or output product, the process does not have to be revalidated. Whether the process is operating in a state of control is determined by analyzing day-to-day process control data and any finished device testing data for conformance with specifications and for variability.

When changes or process deviations occur, the process must be reviewed and evaluated, and revalidation must be performed where appropriate [820.75(c)]. Review, evaluation, and revalidation activities must be documented.

Processes may be routinely validated on a periodic basis; however, periodic validation may not be adequate. More important is appropriate monitoring so that if problems develop or changes are made, the need for immediate revalidation is considered.

REFERENCES

1. Guideline on General Principles of Process Validation, May 1987, FDA, CDRH/CDER
2. Journal of Validation Technology, Vol. 1, No. 4, August 1995

The Validation Process

Overview

Introduction

This chapter looks at the validation process. Note: This validation process is used to validate a specific computer system. It may be done on an existing computer system or on a new computer system.

Purpose

The purpose of the validation process is to provide a high degree of assurance that a specific process (or in this case computer system) will consistently produce a product (control information or data) which meets predetermined specifications and quality attributes.

The Validation Facets

The validation effort consists of 5 specific facets or processes, each alone, would not constitute a validation.  However, depending on the specifics of the application, system or process, would depend on which facets would be required.  There following facets are: ·  The Validation Master Plan (VMP) ·  The Project Plan ·  Installation Qualification (IQ) ·  Operational Qualification (OQ) ·  Performance or Process Qualification (PQ)

Types of validation

The two types of validation are: ·         Prospective validation: the validation of a new system as it is developed ·         Retrospective validation: the validation of an existing system

Validation process		The validation process and document references are shown below:
Step	Action
1	Establish Team(s)
2	Determine Validation Activities
3	Write the Validation Protocol
4	Specify the System Development Details
5	Perform Qualification Activities
6	Develop/Review Controls and Procedures
7	Certify the System
8	Review Periodically

Steps 1 to 8

Introduction

This topic provides an overview of the validation process.

Step 1: Establish team(s)

The first step in the validation process is to establish the System Validation Team and if required the System Validation Steering Team. These are the teams that will be responsible for the validation process.

Step 2: Determine validation activities

The second step in the validation process is to determine and record all of the validation activities that will be undertaken in order to validate the computer system. The validation activities are the exact details or activities that will be required for each of the steps in the validation process. The output from this activity will be the Validation Plan. Example: At step six of the validation process (Develop/Review Controls and Procedures) the exact controls and procedures that will be required to keep the computer system validated will be determined and recorded. Note: The type and number of validation activities will depend on the nature of the computer system that is being validated.

Step 3: Write the Validation Protocol

The third step in the validation process is to write the Validation Protocol. The Validation Protocol describes the procedure and the steps within the procedure that will be followed in order to validate the system. The Validation Protocol must also provide a high level description of the overall philosophy, intention and approach.

Step 4: Specify the system development details

The fourth step in the validation process is to specify the system development details. You should specify to the supplier or developer of a system that they must have: ·         a good methodology in order to develop a system ·         a formal quality management system for the development, supply and maintenance of the system You may need to specify to the supplier or developer the types of items you want to see - this could be done in the form of a Quality Plan. These items will help you ensure that the supplier or developer has a good methodology and formal quality management system in place. Examples: Items that will help you ensure a good methodology and formal quality management system include: ·         quality management procedures ·         life cycle definition ·         specifications, for example user requirements specification and functional specification ·         documentation controls and various items of documentation, for example user manuals and administrator documentation ·         testing procedures If the computer system is a new one, then the system development requirements will be identified prior to system selection/development. If the computer system is an existing one, then the system development requirements will still be identified and used as a basis against which to evaluate the system.

Step 5: Perform qualification activities

The fifth step of the validation process is to perform the qualification activities, which are comprised within the validation process. Some examples of these qualification activities include: ·         Supplier audit ·         Specification qualification ·         Design qualification ·         Installation qualification ·         Operational qualification ·        Performance qualification

Step 6: Develop / review controls and procedures

The sixth step of the validation process is to develop/review controls and procedures. If the computer system is a new one, then you will need to develop the controls and procedures, or check the suitability of existing generic procedures applicable to the site or department. If the computer system is an existing one, then you will need to review the controls and procedures and update them if required.

Step 7: Certify the system

The seventh step of the validation process is to certify the system. This step is where you certify that the validation deliverables have met the acceptance criteria that were described in the Validation Protocol. When you certify the system you should prepare a validation report. The validation report should outline the details of the validation process. Examples of details that should be outlined include: ·         what was done and the results that were obtained ·         any special considerations ·         whether the validation procedure (as described in the Validation Protocol) was followed ·         a summary of all documentation that was generated ·         the location of the validation documentation ·         the retention period for the documentation

Step 8: Review periodically

The eighth and final step of the validation process is to review the system validation periodically. The system should be reviewed periodically to provide additional assurance of validation. There should be documentation outlining the details of how the review is to be done and what the review should cover. The end result of a review should be a summary of the review and a recommendation as to what to do next.

Timing and Documentation

Introduction

This topic looks at the timing of the validation process and documentation.

Timing

Ideally, the validation process begins at the inception of the system selection or design process. It then proceeds alongside the system development and is completed prior to implementation of the system. Many aspects of computer systems validation are just "Good Informational Resources (IR) Practice" and as such should occur anyway during the implementation of a system. For many reasons, a system may not have been validated until after it has been in use for some time. The basic validation process is the same as for a new system. The timing of some of the validation activities may, however, differ. Note: Retrospective validation is becoming increasingly unacceptable to regulatory inspectors. New systems should be validated before use.

Timing for a new system

The steps in the validation process, and their associated validation activities are performed in parallel with the system development life cycle and reference the development documentation as it is produced.

Timing for an existing system

For existing systems, the validation activities will still follow the development life cycle but will reference the development documentation retrospectively.

Example

An example of the parallel between system development and validation activities is shown below. * Functional Specification can comprise mechanical, electrical and software functional specification for systems embedded in equipment ** Systems embedded in equipment with significant control and monitoring instrumentation *** Testing carried out by supplier can form part of subsequent qualification activities if adequately controlled. This can help reduce the amount of testing needed later, particularly at operational qualification.

 

Documentation

Every step in the validation process, and the activities within the steps, requires documented evidence that the steps or activities have been completed. The table below shows the documents that must be generated at each step. Note: In some cases some of these documents may not be required.

Step	Action	Documents Generated
1	Establish Validation Team(s)	·         Team Charter ·         Terms of Reference ·         Role Definition ·         Team Organization Chart
2	Determine Validation Activities	·         Validation Plan
3	Write the Validation Protocol	·         Validation Protocol
4	Specify the System Development Details	·         Systems Development Life Cycle documentation
5	Perform qualification activities	·         Supplier Audit Report ·         In-house Audit Report ·         Source Code Review Report ·         Specification Qualification Report ·         Design Qualification Report ·         Installation Qualification (IQ) Protocol ·         IQ Results ·         IQ Summary Report ·         Operational Qualification (OQ) Protocol ·         OQ Results ·         OQ Summary Report ·         Performance Qualification (PQ) Protocol ·         PQ Results ·         PQ Summary Report
6	Develop/Review Controls and Procedures	·         SOPs (Standard Operating Procedures) ·         Training procedures ·         Training records
7	Certify the System	·         Validation Report ·         Validation Certification
8	Review the System Validation Periodically	·         Periodic Review Procedure ·         Periodic Review Audit Report

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Outsourcing Critical Cleaning

Considerations for custom cleaning and packaging services

By Michael Lehtinen

The pharmaceutical industry is constantly reviewing strategies to improve profitability and process efficiency. Many technological advances have been — and continue to be — implemented to help facilitate this. However, outsourcing is an area, particularly in the current financial climate, that is providing value across the board, from R&D through to manufacturing. Regulatory compliance is influential in this shift; it is essential for risk prevention, yet can be time-consuming, dragging on internal resources and potentially impacting production run-time. Critical cleaning is one area that faces such challenges and is often under review.

Photo courtesy of EP Scientific, part of Thermo Fisher Scientific

Any pharma/biopharma company utilizing critical working environments needs to ensure that all equipment is fully validated and, where appropriate, certified ‘clean.’ This is the case for both the upstream R&D laboratory and the downstream manufacturing facility. In the manufacturing setting, depyrogenation and sterilization are a matter of paramount importance to production quality; maintaining a clean environment and utilizing certified clean vials and containers ensures the ultimate provision of microbiologically safe and uniform parenteral pharmaceuticals.

Beyond patient safety, remaining compliant to the stringent regulatory requirements is also of significant financial benefit to a pharma company in both the long and short term. A re-run of production due to contamination — or worse, a withdrawal of a product batch from the market — has massive cost implications in terms of time, materials, production and reputation. In order to gain assurance that the complex regulations associated with cleaning are consistently met and that containers for critical environment applications are processed and certified to exacting specifications, companies can outsource this time-consuming task.

What Does Critical Cleaning of Containers Involve?

Although sample tubes, containers and associated closures are not necessarily high value products, what they contain is. Consequently, ensuring these are as clean as the processes and environments in which they are used requires the understanding and adoption of proven methods to guarantee essential GMP quality assurance and traceability. An in-depth appreciation of the applications for which the containers will be used is, therefore, necessary to ensure that the best cleaning process is implemented, while keeping costs to a minimum. There are a variety of container-cleaning methodologies available, all designed to meet different cleaning requirements these include: surface modification, via silanization or siliconization, depyrogenation, sterilization and low particulate cleaning.

Following cleaning, every batch of containers must be tested and certified for cleaning validation purposes. There are a large number of potential analytical parameters necessary to enable certification. These will depend on the potential application of the container, but can include GC, GC/MS, ICP/MS, AA, and GF-AA, as well as other testing techniques such as those for endotoxin and sterility testing. Finally, to meet traceability requirements, all raw data and benchwork must be retained and samples from every lot tested should ideally be archived for 10 years.

Knowledge of appropriate safety and regulatory requirements is also essential, not only for current regulations, but also how they may change in the future. The pharmaceutical industry requires a wide selection of chemicals and processes to achieve better contamination control at lower costs. However, health and environmental concerns have resulted in restrictions on the use of certain chemicals and processes. To foresee future trends, an understanding of how the approaches of regulatory agencies may change over time is advantageous.

Why Outsource It?

It is evident that cleaning newly manufactured drug product containers to appropriate specifications is a costly process in terms of time, resources and in-house expertise. Consequently, this task has increasingly been outsourced during the last three to five years. Since outsourcing companies have the expertise to ensure that all containers are compliant with various regulations, such as those from the FDA and U.S. Pharmacopeia (USP), in-house expertise is no longer essential. Costs can, therefore, be saved on training and laboratory researchers are freed to focus on product development.

Furthermore, many pharmaceutical laboratories require a variety of different batch sizes depending on the stage in the process, ranging from discovery through to scale-up. For example, a new drug still in the discovery stages or clinical development may only require a few dozen containers to package the product under development. However, even though such experiments are only being performed on a small scale in the laboratory, the protocols adopted should be similar to those used in final production to ensure that results are not compromised by laboratory grade containers. As data is accumulated the number of experiments and tests increases, driving the need to a few hundred containers. However, these volumes are still very small when compared to the equipment used to process the final product. The process of loading and setting up a high speed line, which is likely to be installed in a large pharmaceutical company, is far greater than that of actually running the product through the process. That is, if the setup time on the processing equipment is one hour and the machine is capable of producing 10,000 vials per hour, the inefficiency is evident if only a few hundred containers are required. The ability to outsource the supply of flexible quantities is invaluable. This ensures the provision of smaller quantities of product until the need for the item reaches a point of efficiency, and the production of final product on large scale equipment, which may exceed 100,000 vials per day, can move “in house”.

Outsourcing of custom cleaning and packaging, therefore, has some clear advantages for the pharmaceutical industry:

• Access to critical cleaning expertise
• Production of containers to exacting regulatory specifications is not a distraction from the company’s product expertise
• Economy of scale
• Accommodation of flexible demands and customization for new applications
• Testing, full documentation and ‘cradle to grave’ traceability

Assessing Your Needs

Each of the above is a sufficient reason for looking to outsource critical cleaning of drug product containers and packaging, but how should the appropriate supplier be chosen? There is no single answer. However, one good starting point would be reduction in risk, both in terms of safety and financially. The various cleaning options should then be weighted according to their influence on risk to the whole business. Requirements to be considered may include the following:

How ‘clean’ is your process?

USP describes limits and methods of analysis for a variety of contaminants. The key regulations relating to the cleaning of containers are: USP 788 for particulate matter in injections, USP 643 regulating Total Organic Carbon (TOC) as an indirect measure of organic molecules, USP 85 relating to acceptable levels of bacterial endotoxins, and USP 71 regarding sterility testing. Will the cleaning processes available ensure that all critical cleaning requirements are met, or even exceeded, cost effectively?

What cleaning methodologies do I need?

Table 1 provides a breakdown of the types of cleaning options available for differing applications.

Table 1: Types of cleaning options available for different cleanroom process applications

Advice and assistance required?

Many API (Active Pharmaceutical Ingredient) manufacturing companies are comfortable with meeting regulatory requirements and will simply outsource for purposes of flexibility of volume. However, there may be companies that are required to supply an intermediate pharmaceutical compound. Although the product itself is not pharmaceutical grade, it is required to meet the expectations of the API manufacturer. This means that the product can be manufactured in an industrial environment, but should have final packaging that meets the strict requirements set by the API manufacturer. These may be guidelines on particulate matter or trace compounds. This is where an expert custom cleaning company can assist by providing the correct level of cleaning to match the customer’s price with their needs.

Help! I need greater throughput now!

The following example demonstrates how this can be rapidly addressed. A contract pharmaceutical manufacturer that fills a product, such as the influenza vaccine, has an established production line capable of meeting a desired throughput. When the swine flu pandemic struck in the fall of 2009, the demand for flu vaccines dramatically increased. While the production of the liquid vaccine was scaled up to meet the demand, the ability of the equipment to process the containers was insufficient. Outsourcing container processing was an opportunity to supplement the supply of the packaging to ensure adequate quantities could be produced to rapidly meet the temporary peak in demand.

I need a customized product

The development of a new application may result in the need for a new and innovative solution, particularly due to the growing need for higher standards of purity demanded by today’s ultra-sensitive analytical instrumentation. Frequently, pharma and biopharma customers require expertise in resolving the difficult challenge of sourcing containers as clean as the facilities in which they will be used. Here the key questions to be asked are:

• Will you send your own materials or do you require them to be supplied?
• What cleaning process(es) do you need?
• What packaging configuration is required? – e.g. Cleanroom bag, autoclave bag, foil wrap, etc.
• What are your certification requirements? – e.g. Certificate of Analysis, Certificate of Processing, selected testing by USP methods, Certificate of Sterility, etc.

Finding the best supplier for you

Once you have decided upon your key requirements, you now need to decide on the best supplier to service these. It is probable that the basic requirements for supply of a clean container can be met by any of several companies in the industry. However, confidence in the quality of containers supplied for use within critical areas is key, along with the ability to understand, advise on and meet very specific needs.

Figure 1: Flow diagram demonstrating how utilizing external resources for custom cleaning and packaging services frees up valuable internal resources

Trust & reputation

Evidence of experience and continuous performance in meeting critical cleaning regulations should be a crucial element in the decision making process. Furthermore, a company should be able to demonstrate that it has never had any instances of product that has caused illness. A good reputation must be earned by building up trust with customers, and an open-door audit policy is an excellent way of developing this, whilst also ensuring that manufacturing companies can satisfy regulatory needs without compromise.

GMP quality compliance

Outsourcing to a reputable company can significantly decrease the amount of in-house compliance work that need be undertaken. If the outsourced company can offer ‘cradle to grave’ traceability through batch record tracking, this ensures that, should the FDA have any questions at any time, the necessary paperwork will always be available to provide an immediate answer. In addition, manufacturing processes and cleanroom facilities that ensure products are handled in Class 100/10 environments can only further secure product quality.

Flexibility

The ability to provide varying quantities of customized end products through processing, packaging and certification to meet the exact requirements of a customer is highly advantageous, particularly if the customer has its own specific containers that need custom cleaning. Furthermore, a supplier that can interact at the customer’s convenience is also an ideal scenario. For example, the ability to visit a customer’s facility and undertake all protocols and validation on its behalf could be seen as ideal.

Return on investment

Selecting a contract cleaning services company that can provide flexibility, confidence and efficiency is no mean feat and there are many considerations to take into account. We have looked at the required expertise, capabilities and services, however, it is ultimately the bottom line — and potential for savings that can be demonstrated by such a company — that is often the critical factor in the decision making process. Figure 1 highlights where outsourcing an expert critical cleaning company can certainly deliver return on investment (ROI). Indeed, value is added since most discovered compounds do not make it to commercialization. This is because internal resources only have an ROI if the product is a success; the truth is that fewer than one in 10,000 are successful.

Validating Sterile Filtration: Overcome the Fear of Failure 4

“I need an absolute 0.1- or 0.2-µm-rated filter.”
 
 As a former FDA authority, since retired, once observed, “The word ‘absolute’ should be used only in conjunction with vodka.” Absoluteness implies a complete independence from conditions, an inherent ability to retain particles larger that than the filter’s pore size rating, regardless of any other considerations. Without a complete knowledge of the properties of the particles and filter pores at our disposal, the statement is devoid of technical significance or guidance. It may, perhaps, be used in ignorance (although cynics may suspect that its utility derives from marketing efforts, a practice not unknown in the competitive world of sales.)
Control vs. Fear
As Sandman elucidated, human beings like to be in control, and, if this status cannot be achieved, may move rapidly to fear. Unfortunately, when sterile filtration is concerned, fear can result in the installation of wasteful, unnecessary safety nets that can create more problems than they solve.
Being in control is the desired state, and such control can only come from process validation studies. Their authority is at least as old as Lord Kelvin’s basic scientific principle, “When you can measure what you are speaking about, and can express it in numbers, you know something about it.”
It speaks to validation. In sterile filtration, as in most areas of pharmaceutical manufacturing, science-based validation is the best cure for fear.

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References
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13. PDA/FDA Special Scientific Forum, Bethesda, MD; Validation of Microbial Retention of Sterilizing Filters, July 12-13, 1995.
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15. Agalloco, J., Letter to the Editor—re: “It just doesn’t matter, It just doesn’t matter, It just doesn’t matter.” PDA Journal of Science and Technology. Vol 52, No. 3, pp. 149-150.