Qualification and Validation Scope

• Documented evidence to prove that, e.g.

  - Premises

  - Supporting utilities

  - Equipment have been designed in accordance with GMP

• Also referred to as Design Qualification (DQ) where appropriate

Documented evidence should be provided that prove that e.g.

Premises

Supporting utilities such as water systems, air handling systems, gas supply, compressed air (where these are relevant)

Equipment have been designed in accordance with GMP and meet their user requirements/design specification needs.

Also referred to as Design Qualification (DQ) where appropriate.

Qualification and Validation Principle

• Essential part of GMP

• Manufacturer to identify what qualification and validation work is required

• Prove that critical aspects of work are controlled

• Key elements of qualification and validation defined and documented

Validation is an essential part of GMP. There are two main reference sources in the WHO documentation relating to validation. Firstly, the WHO GMP text covers validation in section 4 of the general GMP text. Then there is a second document on Validation that describes recommended practices for validation and qualification (40^th Report of the Expert Committee).

Manufacturers should identify what validation and qualification work should be done. All systems, equipment, processes, procedures should be reviewed and the manufacturer should decide what qualification and validation work needs to be performed. The intention is to prove that all critical aspects of the work are controlled, and perform as required.

Validation and qualification work must be documented.

Qualification and Validation Definitions

Validation

• Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results

Qualification

• Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results

(Validation usually incorporates the concept of qualification)

There are a number of definitions of validation - all of which say the same thing in different ways. The definition on this slide is the one given in the WHO GMP texts. There is a more expanded version in the WHO text on the validation of manufacturing processes:

The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensure that the manufacturing processes - including equipment, buildings, personnel and materials - are capable of achieving the intended results on a consistent and continuous basis.

Validation is the establishment of documented evidence that a system does what it is supposed to do.

There are three key points to take from these definitions:

1. The evidence must be documented. (The results of the validation must be recorded).

2. Validation applies to several aspects of manufacturing, including e.g. process development, materials, personnel and equipment).

3. It should demonstrate that the system does what is expected of it.

Validation is carried out against a set of criteria that are defined in advance. These criteria are detailed in predefined protocol documents.

Validation protocol and report

A suggested scheme for the validation protocol and subsequent report concerning a particular process is shown below:

Part 1. Purpose (the validation) and prerequisites
Part 2. Presentation of the entire process and subprocesses, flow diagram, critical steps/risks
Part 3. Validation protocol, approval
Part 4. Installation qualification, drawings
Part 5. Qualification protocol/report

5.1 Subprocess 1

5.1.1 Purpose

5.1.2 Methods/procedures, list of manufacturing methods, SOPs, and written procedures, as applicable

5.1.3 Sampling and testing procedures, acceptance criteria (detailed description of, or reference to, established procedures, as described in pharmacopoeias)

5.1.4 Reporting

5.1.4.1 Calibration of test equipment used in the production process

5.1.4.2 Test data (raw data)

5.1.4.3 Results (summary)

5.1.5 Approval and requalification procedure

5.2 Subprocess 2 (same as for Subprocess 1)

5.n Subprocess n

Part 6. Product characteristics, test data from validation batches

Part 7. Evaluation, including comparison with the acceptance criteria and recommendations (including frequency of revalidation/requalification)

Part 8. Certification (approval)

Part 9. If applicable, preparation of an abbreviated version of the validation report for external use, for example by the regulatory authority

The validation protocol and report may also include copies of the product stability report or a summary of it, validation documentation on cleaning, and analytical methods.

1. Types of process validation

Depending on when it is performed in relation to production, validation can be prospective, concurrent, retrospective or revalidation (repeated validation).

Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps: these are then evaluated on the basis of past experience to determine whether they might lead to critical situations.

Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set. The trials are then performed and evaluated, and an overall assessment is made. If, at the end, the results are acceptable, the process is satisfactory. Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory. This form of validation is essential in order to limit the risk of errors occurring on the production scale, e.g. in the preparation of injectable products.

Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. The first three production-scale batches must be monitored as comprehensively as possible.¹The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.

¹ This careful monitoring of the first three production batches is sometimes regarded as prospective validation.

Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product.

Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated. Recorded difficulties and failures in production are analysed to determine the limits of process parameters. A trend analysis may be conducted to determine the extent to which the process parameters are within the permissible range.

Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. Retrospective validation may then be useful in establishing the priorities for the validation programme. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule. For tablets which have been compressed under individual pressure-sensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. On the other hand, it should not be applied in the manufacture of sterile products.

Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.

Revalidation may be divided into two broad categories:

• Revalidation after any change having a bearing on product quality.
• Periodic revalidation carried out at scheduled intervals.

Revalidation after changes. Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent.

Revalidation after changes may be based on the performance of the same tests and activities as those used during the original validation, including tests on subprocesses and on the equipment concerned. Some typical changes which require revalidation include the following:

• Changes in the starting material(s). Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product.

• Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability.

• Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality.

• Changes in equipment, including measuring instruments, may affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process.

• Changes in the production area and support system, e.g. the rearrangement of manufacturing areas and/or support systems, may result in changes in the process. The repair and maintenance of support systems, such as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the manufacture of sterile products.

• Unexpected changes and deviations may be observed during self-inspection or audit, or during the continuous trend analysis of process data.

Periodic revalidation. It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. Similarly, equipment wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made.

The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during in-process and finished product testing after the latest validation, aimed at verifying that the process is under control. During the review of such historical data, any trend in the data collected should be evaluated.

In some processes, such as sterilization, additional process testing is required to complement the historical data. The degree of testing required will be apparent from the original validation.

Additionally, the following points should be checked at the time of a scheduled revalidation:

• Have any changes in master formula and methods, batch size, etc., occurred? If so, has their impact on the product been assessed?

• Have calibrations been made in accordance with the established programme and time schedule?

• Has preventive maintenance been performed in accordance with the programme and time schedule?

• Have the standard operating procedures (SOPs) been properly updated?

• Have the SOPs been implemented?

• Have the cleaning and hygiene programmes been carried out?

• Have any changes been made in the analytical control methods?

Validation Requirements for Drug Products and Active Pharmaceutical Ingredients

Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08)

This guidance document represents the Food and Drug Administration's (FDA) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations.

BACKGROUND:

This Compliance Policy Guide (CPG) explains the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine (CVM) enforcement policy regarding the timing of the completion of certain process validation activities for the products covered by this CPG.

This policy guide covers sterile as well as non-sterile manufacturing processes, but it does not address the methods and controls designed to ensure product sterility (e.g., aseptic fill validation). New drug applications for sterile products include information about the intended sterilization or aseptic processing procedures. The Centers evaluate this information as part of the application review process. CDER, CBER, and CVM may also issue assignments to district offices to audit and assess the filed information as well as any additional information that demonstrates the adequacy of the sterile process.

This CPG does not address products approved by a Biologics License Application (BLA) or recombinant protein drug products submitted in a New Drug Application (NDA).

Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21 CFR 211.100 and 211.110), and is considered an enforceable element of current good manufacturing practice for active pharmaceutical ingredients (APIs) under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. A validated manufacturing process has a high level of scientific assurance that it will reliably produce acceptable product. The proof of validation is obtained through rational experimental design and the evaluation of data, preferably beginning from the process development phase and continuing through the commercial production phase. Refer also to the Guideline of General Principles of Process Validation (May 1987, originally published by CDER, CBER, and CDRH and presently recognized by CDER, CBER, and CVM). (Note: The guideline is under revision as of the date of this CPG.)

Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval product distribution. Normally, this is achieved after satisfactory product and process development, scale-up studies, equipment and system qualification, and the successful completion of the initial conformance batches. Conformance batches (sometimes referred to as "validation" batches and demonstration batches) are prepared to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make acceptable product. Prior to the manufacture of the conformance batches the manufacturer should have identified and controlled all critical sources of variability.

POLICY:

1. Conformance batches:

New drug applications may be approved by the Center prior to the completion of the initial conformance batch phase of process validation. The manufacture of the initial conformance batches should be successfully completed prior to commercial distribution, except as identified below.

2. Inspection of validation activities during a pre-approval inspection:

If a pre-approval inspection is performed, the inspection team should audit and assess any available process validation protocols, activities, data, and information, whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed validation efforts include data of questionable integrity or demonstrate that the process is not under control and the firm has not committed to making appropriate changes. Refer also to the Center pre-approval inspection compliance programs for additional guidance.

If during a pre-approval inspection, process validation activities are found significantly deficient for an approved product made by a process similar to that of the subject of the pre-approval inspection and for which a warning letter or regulatory action will be proposed, the district should recommend withholding approval of the application.

3. Inspection of validation activities during a post-approval inspection:

If the initial conformance batch validation activities for a particular approved product were not substantially inspected and found satisfactory during the pre-approval inspection, the district should cover this activity for the approved application or a substantially similar process/product during the next routine CGMP inspection (see Compliance Programs 7356.002 for human drugs, and 7371.001 for animal drugs).

The district should inspect the firm’s validation activities for the new product within the first year of manufacture at commercial scale (if not inspected during the pre-approval inspection) if any of the following conditions apply:


1. the new drug is the first produced by the manufacturing site;
2. the firm has had previous problems validating a similar process for another product;
3. the product is manufactured by equipment or process that is substantially different from equipment or processes previously used by this firm; or,
4. the product is made by a process involving inherently variable unit operations or complex operations or procedures (see Compliance Programs 7356.002 for human drugs, and 7371.001 for animal drugs; and consult further with the Center's reviewing office for the product being inspected and/or the Office of Compliance subject contact for further guidance).

If none of the above conditions apply, the district should evaluate validation activities for new products during the next routine CGMP program inspection (7356.002). Alternatively, for sites with a history of successful validation efforts for related products made by similar processes the district may request the process validation protocol and report to be sent to the district office for audit and assessment. Based on the review of this information, additional on-site inspection, evaluation, and documentation of the information received may, or may not be conducted at the district’s discretion unless directed otherwise.

If a firm’s validation activities for the new product are found to have significant deficiencies (e.g., the initial conformance batch phase was not completed, the protocol was not followed or is inadequate, or validation data indicates process is not adequate), and one or more batches have been distributed, the district office should recommend regulatory action.

Seizure of distributed batches should be considered when there are significant deficiencies with validation or the evidence demonstrates the product does not comply with specifications. Injunction should be considered when there are significant deficiencies or data demonstrating the process is not capable of producing product meeting the established specifications.

4. Completion of initial conformance batch manufacture prior to commercial distribution:

For some products, the completion of the initial conformance batch phase of process validation before the distribution of any one batch would require the manufacture of unneeded batches (e.g., certain orphan drug products), which would not be in the interest of public health. In addition, the completion of multiple batches before first distribution may also be impractical for a product with a very short shelf-life or that is intended for limited use (e.g., some radiopharmaceuticals). Therefore, the need to manufacture multiple conformance batches in advance of initial product distribution may not be needed under these circumstances. In such cases, product distribution may have occurred concurrently with the release (or approval for release) of each conformance batch.

The agency’s evaluation of a firm’s decision to release batches concurrent with the manufacture of the initial conformance batches should include review and/or audit and assessment of:


1. the firm’s basis for justifying the distribution of individual batches prior to completion of the initial conformance batches (to include review of the product/process development effort);
2. the firm’s protocol/plan and available data to verify that there are adequate batch controls and testing prior to release for distribution of each batch, and provides for adequate and timely assessment of the validity of the process once all initial conformance batches have been manufactured; and,
3. the firm’s program for monitoring distributed batches and provisions for a rapid response to information suggesting the process is not under control (e.g., subsequent batch failures, production problems related to process design or equipment performance, complaints).

Advanced pharmaceutical science and engineering principles and manufacturing control technologies can provide a high level of process understanding and control capability. Use of these advanced principles and control technologies can provide a high assurance of quality by continuously monitoring, evaluating, and adjusting every batch using validated in-process measurements, tests, controls, and process endpoints. For manufacturing processes developed and controlled in such a manner, it may not be necessary for a firm to manufacture multiple conformance batches prior to initial distribution. Agency staff (field and Center) should discuss the need for conformance batches prior to distribution with the designated agency contacts when inspecting firms employing these advanced pharmaceutical science and engineering principles and control technologies.

The district should consult with the appropriate agency contact before initiating regulatory action based on insufficient validation under the above circumstances.
5. Active Pharmaceutical Ingredients:

Under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Act, process validation, including the manufacture of initial conformance batches, is also expected for Active Pharmaceutical Ingredients (APIs), but the specific expectations differ somewhat from those required for dosage form products. Refer to the Guidance for Industry, Q7A, GMP Guidance for Active Pharmaceutical Ingredients, issued August, 2001, for details.

If the API for an application under review is already used in other approved or marketed dosage form products, and is being made by substantially the same process and scale as for the application under consideration for approval, the inspection should cover full process validation data and activities (including conformance batches), unless covered during a previous inspection of the API manufacturer. If validation is covered and significant deficiencies are found, the district is to recommend withholding approval of the dosage form application and consider proposing action to address the use of that API in other dosage form products.

If the API for an application under review is a new molecular entity or is being manufactured by a process substantially new in design or scale to the site of manufacture, approval of the dosage form incorporating the API is not to be delayed by the performance of initial conformance batches for the API. However, the inspection team is to audit and assess any available process validation protocols, activities, data, and information whether or not completed, and report to the firm any deficiencies. The district should recommend withholding approval of an application if any completed API validation efforts include data of questionable integrity or demonstrate that the API process is not under control and the firm has not committed to making appropriate changes.

Some biotech NDAs include information about the validation of the manufacturing process for the API, and this information is reviewed in conjunction with the other chemistry, manufacturing, and controls information in the application. In these cases, the inspection team should audit the accuracy and completeness of the data and information submitted to the application. Potentially objectionable findings should be handled consistent with the applicable compliance program and include consultation with the Center reviewer and/or compliance officer before making any formal objection to the firm.

If during a pre-approval inspection of the API manufacturer, process validation activities are found significantly deficient for an API made by a process similar to that of the API under inspection and for which a warning letter or other regulatory action will be proposed, the district should recommend withholding approval of the dosage form application. The district should also recommend withholding approval if the API firm has not established or is not following an adequate initial conformance batch validation plan/protocol or when the process is not under control as demonstrated by repeated batch failures due to manufacturing process variability.

If batches have been distributed, the district should consider recommending an appropriate regulatory action.

NOTE: This compliance policy guide (CPG) also applies to pre-market approval applications submitted to the Center for Veterinary Medicine (NADAs or ANADAs). The CPG reference may be found at Sec. 638.100 (7125.38).

Concurrent Validation

FDA considers concurrent validation to be a subset of prospective validation. The Agency recognizes that in a limited number of cases it may be impossible to complete validation of an API process in a timely manner when data from replicate production runs are unavailable because: - Only a limited number of API batches intended for clinical or orphan drug products have been produced; - API batches are produced infrequently (e.g., limited market demand, complex multi-step API processes with long completion times); or - APIs batches are produced by a modified process (e.g., a validated process goes outside the proven acceptable range of a critical operating parameter and the batch is subjected to intensive analytical tests).

In such cases, firms should do all of the following: - Document the reasons for not completing process validation before shipment of the API; - Perform all of the elements of prospective validation, as discussed in Section XIII.C., exclusive of replicate production run testing, before releasing any batch for distribution; - Conduct intensive in-process monitoring and testing, along with intensive testing of each API batch, to show that each production run resulted in an API meeting its predetermined quality characteristics and specifications (such data should also be assessed under the validation protocol to determine consistency of the process);.

- Provide for the Quality Control unit to evaluate batch production records, in-process controls, and analytical data from each process run to determine whether each batch should be released.

The level of intensive in-process and final API testing should be greater than levels for validated routine production runs, and should only be reduced to routine levels after the process has been determined to be validated. In addition, data from production runs that are evaluated as part of the validation studies should encompass the operating ranges that are approved for use during routine process control.

The Agency cautions that this validation approach should be applied with discretion so as not to: - Unduly delay completion of, or avoid performing, meaningful validation; or - Distribute API batches manufactured before completion of validation for a prolonged period of time.

This approach should not be viewed as a viable alternative where the number and frequency of API production runs permit timely completion of validation prior to API distribution. If analysis of data shows that the process used to manufacture the distributed batches was not, in fact, validated, no additional batches should be distributed until corrections have been implemented and the process has been determined to be validated.

Prospective Validation

Prospective validation should be conducted prior to the commercial distribution of an API produced by a new or substantially modified process. This validation approach should involve obtaining and evaluating documented processing and analytical control information for multiple batches manufactured, sampled, and tested according to a preestablished validation plan.

When prospectively validating a process, data from laboratory- and/or pilot-scale batches should identify critical quality attributes and specifications, critical steps, control ranges, and in-process tests. Scale-up batches could be used to generate data to confirm or refine earlier work, and production-scale batches should provide data showing consistency of the process.

The number of process runs should depend on the complexity of the process or the magnitude of the process change being considered. Although three consecutive, successful production lots should be used as a guide, there could be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). If a validation lot fails for reasons unrelated to process performance (e.g., power failure or equipment breakdown), that lot should be removed from the validation study and an additional validation run conducted.

Validated analytical methods capable of quantifying API quality attributes should be used during process validation. Resulting data should be evaluated and included in a validation report approved by the same organizational units that approved the protocol.

The Validation Protocol

A written validation protocol should be established that specifies how process validation will be conducted. The protocol should be reviewed and approved by the quality control unit and other designated organizational units.

The validation protocol should include the following: - Purpose and scope of the validation; - Functions and responsibilities of all organizational units involved in the validation; - Type of validation to be conducted with appropriate justification for type chosen; - Number of process validation runs; - Quality of materials used in the process (e.g., recovered vs. fresh solvents); - Description of the process (e.g., discussion of the chemistry, unit operations, process flow diagram); - All major process equipment used, its type/design, and its installation and operational qualification (IQ/OQ); - The critical quality attributes of the API; - The critical process parameters and operating ranges; - Sampling plans (i.e., sampling points, frequency, quantities, and procedures for collecting samples); - Specifications and test data to be collected; - Acceptance criteria needed to conclude that the validation has been successful; and - Steps to follow in the event of a process validation failure.

The above information need not be incorporated in the validation protocol if the protocol makes specific reference to other documents that contain the information (e.g., COA’s, development reports, and IQ/OQ reports). Any changes to the validation plan should be documented with appropriate justification.

Process Validation Strategy

A written program should be established and followed for validating the manufacturing processes for all APIs. Validation studies should ensure that a specific manufacturing process is capable of performing in a reliable and consistent manner and results in a homogeneous API that consistently meets predetermined specifications.

Validation should embrace steps in the processing of APIs that are critical to the quality and purity of the final API, and should include: - Definition of the API in terms of its critical quality attributes. Among the attributes that should be considered are chemical purity; qualitative and quantitative impurity profiles; physical characteristics such as particle size, bulk and tap density; polymorphic forms; moisture and solvent content; homogeneity; and microbial quality (if the product is susceptible to microbial contamination).

- Identification of process parameters that could affect the critical quality attributes of the API. Critical parameters should be determined by scientific judgement and typically should be based on knowledge derived from research, scale-up batches, or manufacturing experiences.

- Determination of the range for each critical process parameter expected to be used during routine manufacturing and process control. Data to substantiate the ranges for critical process parameters generally should be obtained from laboratory- or pilot-scale batches, unless a specific parameter can only be determined from a production-scale batch.

Examples of processing steps that could be defined by the API manufacturer as critical include: - Phase changes, such as dissolution or crystallization; - Phase separation, such as filtration or centrifugation; - Steps that cause chemical changes; - Steps that alter temperature or pH; - Mixing of multiple raw materials; and - Steps that cause changes in surface area, particle size, bulk and tap density or homogeneity.

Critical process parameters (e.g., reaction times, reaction temperatures, reactant ratios, concentrations, pressures, pH, and impurity levels) should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

Process validation should confirm that the impurity profile for each API is within the limits specified and is comparable to the profile determined during process development or for batches used for pivotal/toxicological studies.

Retrospective Validation

Retrospective validation could be conducted for a well-established process that has been used without significant changes (e.g., changes in raw materials, equipment, systems, facilities, or in the production process) that affect the critical quality attributes of the API. This validation approach should be used only when there is sufficient history on past API batches to demonstrate the process consistently produces acceptable products, and where: - Critical quality attributes and critical process parameters have been identified and documented; - Appropriate in-process specifications and controls have been established and documented; - There have not been excessive process/product failures attributable to causes other than operator error or equipment failure unrelated to equipment suitability; and - Impurity profiles have been established for the existing API.

In addition to the information described in Section XIII.B., the validation protocol should include the batch selection criteria and analytical data that will be evaluated to determine consistency of the process.

The number of batches to review will depend on the process, but, in general, data from 10 to 30 consecutive batches should be examined to assess process consistency. The review should include any batches that failed to meet specifications. All batches within the selected review period should have been manufactured by the same process and have the same documented history of controls and tests as current APIs. Additional testing of retained samples may be warranted to obtain the necessary data to retrospectively validate the process.

Data obtained should be evaluated by appropriate personnel, and a final validation report summarizing the results and appropriate conclusion should be prepared. This report should be reviewed and approved by the organizational units that approved the original protocol.

Retrospective validation could also be employed to provide additional data to supplement prospective validation and either build confidence in a particular manufacturing process or impugn it as test results are received.

What is Validation?

Validation Master Plan. A Validation Master Plan (VMP) is an integral part of a well organized validation project. It documents the company's approach to complex validation projects. The VMP has a broad scope. It clarifies responsibilities, general objectives, procedures to be followed for validation, and it prioritizes multiple validation tasks. It may reference several protocols and procedures to be written in order to conduct the qualification of several different pieces of equipment and different processes. It may also specify schedules for validation and the allocation of resources needed to perform the validation. Your VMP provides a means of communication to everyone associated with the project. It lets management know how the company’s resources are being allocated and when they will see the results. It tells the validation team what they have to do, when they have to do it, and gives them a means of tracking progress. Other groups can find out what the validation team is doing and what their roles are in support of the validation project. FDA can look at the VMP and realize that the validation project is well thought out and organized; that there is a logical reason for including or excluding every system from the validation project based on a risk analysis. VCI’s experience at writing Validation Master Plans can make your project go smoother whether it’s a new, greenfield plant, expansion of an existing facility, or a rearrangement of operating equipment. Click here to read “The Validation Master Plan: How to Write It and How to Make It Work for Your Company “ by Dr. Norm Howe, VCI Senior Partner, and Kristi Musgrave, VCI Senior Validation Engineer.

Process validation. The FDA defines process validation as "establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes." Process validation is a requirement of the current Good Manufacturing Practices Regulations for Finished Pharmaceuticals (21 CFR Parts 210 and 211), Active Pharmaceutical Ingredients (ICH Q7A), and for Medical Devices (21 CFR Part 820). Validation is sometimes mistakenly viewed as a separate component that is squeezed into a gap between mechanical completion and the startup of a project. In fact it should be incorporated into the planning of the project from the outset and systems need to be in place which insure that the process will remain in compliance throughout the lifetime of the plant.

As outlined in the Commissioning and Qualification Baseline Guide of the International Society of Pharmaceutical Engineers a new project should start with a set of User Requirement Specifications (URS). These tell what the new installation is supposed to do. The URS’s should be carefully documented so that any changes can be tracked through the life of the project. A traceability matrix is a common way to accomplish the tracking of changes in User Requirement Specifications. From the URS the designers formulate a Functional Requirement Specification (FRS) which documents how the new installation is supposed to work. After review of the FRS a detail design is developed and the project is built.

Qualifications must follow an approved protocol that includes acceptable ranges and details what will happen if the tested parameters fall outside acceptable limits. There is a good reason for this. Hard experience has shown that decisions made at 3 o’clock in the morning over a recalcitrant pump can be suboptimal. When the protocol is written and approved in the calm before the storm of plant start-up, there is less of a chance that the response to an out-of-range result will be, ‘Get a bigger wrench.’

Whether your next validation project is large or small VCI can guide you through to a successful conclusion.

Process Characterization. Before validating a process you must first characterize it. You start by defining the boundaries of the process. But the most important part is to truly understand your technology. What are the Critical Process Parameters, ie., the inputs that really determine product quality? Much of this understanding can come from your process development work and it is given to you in the design transfer documents. However, a complete understanding of the process can come only with your production equipment.

Computer and Automated Controls Validation. Prequalification. A new project should start with a set of User Requirement Specifications (URS). These tell what the new installation is supposed to do. The URS’s should be carefully documented so that any changes can be tracked through the life of the project. A traceability matrix is a common way to accomplish the tracking of changes in User Requirement Specifications. For large automation projects like Distributed Control Systems the URS should be a separate document. For imbedded Programmable Logic Controllers it should be incorporated into the equipment URS. A loop list is generated and data backup systems are defined at this point in time. From the URS the designers formulate a Functional Requirement Specification (FRS) which documents how the new installation is supposed to work. It summarizes all activities the software will perform and should include early definitions of inputs, outputs, calculations and applications. The selection of the control system is documented. After review of the FRS a detail design is developed including loop diagrams and the IQ/OQ test plan.

21 CFR Part 11, Electronic Signatures/Electronic Records. Part 11 provides criteria for acceptance of electronic records and signatures by FDA. It allows the use of a wide array of electronic technology. Although much confusion surrounds 21 CFR Part 11 it is in one way quite simple. Conceptually FDA wants the same security, traceability, and many other capabilities that are inherent in a paper system. For instance, if an error is discovered on a paper document we would draw a single line through the offending entry, note the correction, sign it, date it, and note down the reason for the error. FDA wants the same assurance with electronic systems. That means that the old file cannot be overwritten with the corrected data. Electronic records and electronic signatures must have the same integrity and reliability as paper records and handwritten signatures.

To what electronic data does 21 CFR Part 11 apply? Part 11 applies to all electronic records and signatures that are created, maintained, archived, retrieved, or transmitted that fall under any FDA records requirements in the Food, Drug, and Cosmetic Act, the Public Health Service Act, or the Code of Federal Regulations Title 21. These regulations are known as the Predicate Rules of which the following are of most interest for validation: Finished Pharmaceuticals (21 CFR Parts 210 and 211), Active Pharmaceutical Ingredients (ICH Q7A), and for Medical Devices (21 CFR Part 820). The predicate rules mandate what records must be maintained; the content of records; whether signatures are required; how long records must be maintained, etc. If there is no FDA requirement that a particular record be created or retained, then 21 CFR Part 11 most likely does not apply to the record. VCI can help you determine which of your computer systems are subject to 21CFR Part 11.

Part 11 regulations require controls for audit trails, system operational checks, system authority checks, metadata, and system device checks.

What is 'metadata'? It is 'data about data'. The types of metadata that can be associated with an electronic record may include: details of the record's creation, author, creation date, ownership, searchable keywords, details of the type of data found in the document, and the relationships between different data components. Metadata must be stored as an integral part of the electronic document it describes. More useful information at http://www.21cfrpart11.com/

Laboratory Validation / Analytical Method Validation. Laboratory Validation is a process that is employed to ensure that laboratory test data and results are consistent, accurate and precise. The validation process for test methods, as well as the instrumentation that is used to perform the analysis, have IQ, OQ and PQ protocols. There are eleven main principles to the PQ laboratory test validation protocol. These points are to be applied to each and every laboratory test that is critical to the pharmaceutical manufacturing process as well as the stability program and any process validation. Not all of the eleven principles may apply to each type of testing that is performed, however, a thorough review must be done in order to ensure a complete protocol has been written. VCI's experience with a broad range of analytical methods can make your laboratory validation project run flawlessly.
The eleven PQ principles are listed below:

• Specificity
• Linearity
• Accuracy
• Precision
• Robustness
• Range
• Detection Limit (LOD)
• Quantitation Limit (LOQ)
• Ruggedness
• Selectivity
• System Suitability

Cleaning Validation. This validation is used to show proof that the cleaning system consistently performs as expected and provides scientific data that consistently meets pre-determined specifications for the residuals.

The cleaning validation process must be written into protocols and standard operating procedures which are detailed and specific for the different pieces of equipment and instrumentation used by the facility for each type of drug product produced. Other protocols and SOP's are also required if cleaning is performed based on the type of product manufactured or process used (such as a batch or bulk process or shared versus dedicated equipment).

A final report on the cleaning validation system will attest that the studies and data prove that the process is in control and cleans as expected. This report will also detail when and why revalidation needs to take place. Call on VCI to help you clean up your cleaning validation backlog.

Hazard Analysis and Critical Control Points (HACCP). The HACCP process is a prevention-based food safety system. These HACCP programs are to be designed to prevent the occurrence of potential food safety problems. The system appears to be simple at first glance, however, it requires a methodical, systematic approach. A pre-requisite to a well-developed and implemented HACCP system must be a solid current Good Manufacturing Practices (cGMP) program as well as strongly committed management.

The key to the success of your HACCP program is to have your employees trained and educated on the reasons behind your HACCP plan as well as in current Good Manufacturing Practices (cGMP). Training must also be provided to your employees and management on the importance of food safety and how it applies to them. It will be essential that the unique systems of your plant and facility be considered by your HACCP team and expressed to the plant personnel.
Call VCI at 734-274-4680 to get immediate help with your HACCP plan or email us at Ask VCI to find out how VCI can help you.

Validation of Analytical Assays and Test Methods for the Pharmaceutical Laboratory

By Robert V. Sarrio and Loui J. Silvestri, PhD
AccuReg

Overview

Analytical procedures used to measure the quality of pharmaceutical products span almost the entire range of currentlyavailable technologies and techniques. From immunoassay and electrophoretic techniques used to characterize protein moeities, and chromatographic and potentiometric methods used to evaluate the qualities of small molecules, the variety of procedures (and approaches necessary to prove these methods' validity and usefulness) can be overwhelming. However, when evaluating available procedures to determine which are best for your intended use, it is important to keep in mind that the most important aspect of any analytical method is the quality of the data it ultimately produces.

Perhaps the most useful and widely-consulted guidance in the industry is the USP's General Chapter 1225entitled, "Validation of Compendial Methods". This Chapter opens by referencing the Federal Food, Drug and Cosmetics Act (and hence, stressing the legal status of USP test procedures), then continues with a formal definition of "validation" as it applies to analytical methods. Directly quoted, the Chapter states that "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 requirements for the intended analytical applications."

The most significant point raised by this definition is that the validity of a method can be demonstrated only through laboratory studies. It is not sufficient to simply review historical results; instead, laboratory studies must be conducted which are intended to validate the specific method, and those studies should be pre-planned and described in a suitable protocol. The protocol should clearly indicate the method's intended use and principles of operation, as well as the validation parameters to be studied, and a rationale for why this method and these parameters were chosen. The protocol also must include pre-defined acceptance criteria and a description of the analytical procedure, written with sufficient detail to enable persons "skilled in the art" to replicate the procedure.

Validation Parameters - Assays

USP General Chapter 1225, as well as the ICH Guideline for Industry (Text on Analytical Procedures), provide cursory descriptions of typical validation parameters, how they are determined, and which subset of each parameter is required to demonstrate validity, based on the method's intended use. For example, it would be inappropriate to determine limits of detection or quantitation for an active ingredient using an assay method intended for finished product release. However, if the method was intended to detect trace quantities of the active ingredient for purposes of a cleaning validation study, then knowledge of the detection and quantification limits are appropriate and necessary. For this reason, validation of each assay or test method should be performed on a case-by-case basis, to ensure that the parameters are appropriate for the method's intended use. This is even more important when validating stability-indicating assay methods, because these validations are more complex - for example, they may require forced degradation, samples spiked with known degradates, literature searches, etc.

The following definitions, taken from the ICH Guideline for Industry (Text on Analytical Procedures), will provide a background for subsequent discussion:

Analytical Procedure.

The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include, but is not limited to, the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.

Specificity.

Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically, these might include impurities, degradants, matrix, etc. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s).

This definition has the following implications:

• IDENTIFICATION: To ensure the identity of an analyte.
• PURITY TESTS: To ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e., related substances test, heavy metals, residual solvents content, etc.
• ASSAY (Content or Potency): To provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.

Accuracy.

The closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value, and the value found.

Note: When measuring accuracy, it is important to spike placebo preparations with varying amounts of active ingredient(s). If a placebo cannot be obtained, then a sample should be spiked at varying levels. In both cases, acceptable recovery must be demonstrated.

Precision.

The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility.

Precision should be investigated using homogeneous, authentic (full scale) samples. However, if it is not possible to obtain a full-scale sample it may be investigated using a pilot-scale or bench-top scale sample or sample solution.

The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements. Refer to this month's "The Regulatory Clinic" for a discussion of AccuReg's consensual interpretations of the following terms that express precision:

a. Repeatability. Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.

b. Intermediate Precision. Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.

c. Reproducibility. Reproducibility expresses the precision between laboratories (collaborative studies usually applied to standardization of methodology).

Detection Limit.

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

Quantitation Limit.

The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

Linearity.

The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.

Note: Measurements using clean standard preparations should be performed to demonstrate detector linearity, while method linearity should be determined concurrently during the accuracy study. Classical linearity acceptance criteria are 1) that the correlation coefficient of the linear regression line is not more than some number close to 1, and 2) that the y-intercept should not differ significantly from zero.

When linear regression analyses are performed, it is important not to force the origin as (0,0) in the calculation. This practice may significantly skew the actual best-fit slope through the physical range of use.

Range.

The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.

Robustness.

The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate, variations in method parameters and provides an indication of its reliability during normal usage.

Note: Ideally, robustness should be explored during the development of the assay method. By far the most efficient way to do this is though the use of a designed experiment. Such experimental designs might include a Plackett-Burman matrix approach to investigate first order effects, or a 2k factorial design that will provide information regarding the first (main) and higher order (interaction) effects.

In carrying out such a design, one must first identify variables in the method that may be expected to influence the result. For instance, consider an HPLC assay which uses an ion-pairing reagent. One might investigate: sample sonication or mixing time; mobile phase organic solvent constituency; mobile phase pH; column temperature; injection volume; flow rate; modifier concentration; concentration of ion-pairing reagent; etc. It is through this sort of a development study that variables with the greatest effects on results may be determined in a minimal number of experiments.

The actual method validation will ensure that the final, chosen ranges are robust.

---

Other points to consider include:

System Suitability

In addition, prior to the start of laboratory studies to demonstrate method validity, some type of system suitability must be done to demonstrate that the analytical system is performing properly. Examples include: replicate injections of a standard preparation for HPLC and GC methods; standardization of a volumetric solution followed by assays using the same buret for titrimetric methods; replicate scanning of the same standard preparation during UV-VIS assays, etc. When the method in question utilizes an automated system such as a chromatograph or an atomic absorption spectrophotometer, a suitable standard preparation should be intermittently measured during the sample analysis run. The responses generated by the standard should exhibit a reasonable relative standard deviation. This is done primarily to demonstrate the stability of the system during sample measurements. System suitability for dissolution studies should be performed using both USP non-disintegrating and disintegrating tablets prior to the validation of dissolution methods.

Validity Checks - General Tests

It is important to realize that assays are not the only tests important in evaluating the qualities of a drug product. The USP contains numerous identity tests of a chemical nature. In these types of tests, one should treat a placebo preparation with the reaction reagent to ensure a negative result is achieved. Otherwise, the test has no meaning. Dissolution tests, for instance, should be evaluated for adequate sink conditions (i.e., adequate solubility in an adequate volume of the dissolution media) prior to development.

Protocols

As mentioned earlier, prior to initiating a validation study, a well-planned validation protocol should be written and reviewed for scientific soundness and completeness by qualified individuals. The protocol should describe the procedure in detail, and should include pre-defined acceptance criteria and pre-defined statistical methods. Following approved by the appropriate corporate and Quality Control authorities, the protocol should be executed in a timely manner. A typical assay validation will require the preparation of product placebo(s), standards, and many samples.

How many times should an assay be repeated to ensure "validity"? Although 3 sequential replicates are often considered the "magic number," a far more definitive number is one produced by a sound scientific rationale, usually with the assistance of statistical analyses.

Subsequent to the execution of the protocol, the data must be analyzed with results, conclusions and deviations presented in an official validation summary report. Provided the pre-defined acceptance criteria are met, and the deviations (if any) do not affect the scientific interpretation of the data, the method can be considered valid. A statement of the method's validity should be placed at the beginning of the final summary report, along with the signatures and titles of all significant participants and reviewers.

---

In the final analysis, the purpose of validating methods is to ensure the procurement of high quality data. After all, if the quality of data is questionable, no meaningful conclusions can be reached about the quality of the product - which will have seriously detrimental affects on stability study data reviews, process validation data reviews, and annual batch reviews, to name a few. Time invested in validating analytical methods in the beginning pays big dividends in the long run.