Auditing Process Validation

By : Janet Neelay

Validation is required to ensure that a process, system, material, method, product, piece of equipment, or personnel practice, will meet its intended purpose and function or allow functioning in a reliable, consistent manner. A firm derives little benefit if a thorough understanding of validation remains solely within the validation department.

After four decades of existence, validation is little better understood now than when it was first conceived—beyond the concept of “requiring a minimum of three runs”. The term “validation” may differ in meaning from company to company. Validation is demonstrating and documenting that something does (or is) what it is purported to do (or be).

Challenge of the Auditor’s Role

Resources to support validation may not be the best for adhering to compliance procedures. Start by understanding the SOPs pertinent to validation and, specifically, process validation. The auditor’s role will be to examine executed protocols and reports against internal SOPs and external regulations. In addition to the SOPs governing Process Validation, the auditor needs to know if there have been other commitments against which a process validation should be checked.

• Prior internal audit commitments

• Customer audit commitments

• Internal program initiative commitments (e.g., GMP Program)

• FDA commitments (filing or inspection)

When are Process Validations (or Revalidations) Required?

During R&D, physical and chemical performance characteristics should be defined and translated into specifications, including acceptable ranges, which should be expressed in measurable terms. The validity of such specifications is verified through testing and challenge during development and initial production.

Validation of such processes need not be done before the Regulatory Filing (i.e., NDA, ANDA. Validation commitments may be included in the regulatory filing. The Validation Master Plan should include a periodicity (e.g., bi-annual) and specify revalidation when equipment, or other pertinent element, changes. When Annual Process Review (APR) indicates that “drift” is occurring, revalidation must be done.

FDA Regulations for process controls are included in Part 211—Current Good Manufacturing Practice for Finished Pharmaceuticals , Subpart F—Production and Process Controls , Section 211.100 Written procedures; deviations.

In part, these regulations require written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

Validation Types

There are several different types of validation approaches. The best is “Propsective”, since it is planned for and is, therefore, most favored by the FDA.

•Retrospective:

assesses historical performance; traditionally requires more data, not permitted at some companies, but may be necessary for products that have been in production for a long time and pre-dated current requirements for validation.

•Concurrent:

gathers data as runs are executed; less than ideal due to lack of pre-planning

•Prospective:

planned protocol, pre-validation tasks ensured; FDA-favored

Process Validations (Process Qualifications)

Process validation is 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 characteristics. The intent is to demonstrate that a process repeatedly yields product of acceptable quality. A minimum of 3 consecutively successful cycles—on a given piece of equipment using a specific process—constitutes process and equipment validation. Not only is the process under scrutiny, but the piece of equipment used to deliver that process is as well. Process operating limits should be tested, but not edge of failure. “Robustness” and “worst case” are common goals.

Activities that Occur in Advance of Process Validation

Analytical methods must be validated. Processing parameters and conditions must be specified and approved. There must be an availability of clear and detailed SOPs and Manufacturing Batch instruction which avoid the use of subjective criteria and wide processing ranges (e.g., mix gently for 10 – 60 minutes).

Upstream Tasks to Minimize Variability

Check to ensure that tasks are completed which could add variability to the validation, such as:

–Employee training

–Equipment IQ, OQ, Calibration & Maintenance

–Component specifications

–Environmental requirements (temperature, humidity, controlled air quality)

–Qualification of key production materials

Importance of the Protocol

It is a commitment established by the parties involved with the activity. It involves a description of the activity, the proposed and agreed-upon manner to achieve that goal, the number of runs required to achieve that goal, and the acceptance criteria. It is an FDA expectation that all validation protocols be approved before execution. Typical sources for approval are the department responsible for protocol preparation, the department where the equipment will be installed and the quality group.

Protocol & Acceptance Criteria

Product quality attributes must be detailed in the protocol. “Acceptance Criteria” are often the established Product Specifications. Validation should not be used to establish or optimize processing parameters and specifications. Acceptance Criteria may be more stringent, but should never be less demanding, than the Product Specifications. Watch for subjective statements, since they cannot be validated. Example: …continue to add water until you have a suitable granulation…”

Test conditions should encompass upper and lower processing limits which place the most stress on the system. Key process variables should be monitored and documented. Data analysis should establish variability of process parameters.

FDA’s Perception of the Role of the Quality Unit

Those involved in validation must understand what responsibilities the FDA holds the quality unit accountable for. Ensure that any additional requirements from the quality unit have been met by the executed validation—especially additional testing, repeating questionable tests, and providing more rationale.

FDA Regulations for sampling and testing are included Part 211—Current Good Manufacturing Practice for Finished Pharmaceuticals, Subpart F—Production and Process Controls, Section 211.110 Sampling and testing of in-process materials and drug products

In part, these regulations require that written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to, the following, where appropriate: tablet or capsule weight variation; disintegration time; adequacy of mixing to assure uniformity and homogeneity; dissolution time and rate; clarity, completeness, or pH of solutions.

Failure to Meet Acceptance Criteria

Unless the acceptance criteria are met, or there is a sound justification for not meeting them, the goal is not achieved and the validation has failed. When protocol failure occurs, it is customary to conduct an investigation. The investigation should: identify the assignable cause, identify corrective actions, and restart the activity. The importance of this investigation and identification of corrective actions cannot be overstressed. If the investigation does not identify an assignable cause for the failure, the validation must be restarted.

Validating a Transferred Process

In the age of multi-national corporations, it is not uncommon for an R&D unit to be located in one part of the nation (or globe) and the manufacturing unit in another. Thus, when a process is transferred from one place to another, a number of technology transfer points and documents are generated as prospective validation in order to proceed with validation through the various steps of product development. There are many departments involved and they are usually isolated units. Confusion results unless communication is good. Often, a project management team approach will facilitate inclusion of all affected units and identification of all of the steps involved.

Validation of Transferred Technology

Audit checklists can be used to ensure that important elements of the transferred process were not overlooked or misunderstood. Appropriate participants should have approved the protocol and also the final report. If it isn’t clear to the auditor, it won’t be clear to FDA.

Questions Often Asked During Technology Transfer

Raw Materials

Do specifications exist?

Do they make sense?

Are the test methods reliable?

Are the specifications needed?

What should be specified but isn’t?

What is the source of raw materials?

Are there more sources?

What is the grade to be used?

Are the grades interchangeable?

Equipment

Does the plant have the proper equipment?

Are the batch size and equipment matched?

Does an alternate supplier exist?

Can the equipment in the plant be used—even though the principle of operation is not yet specified?

Process Parameters

Are the set points too narrow?

Are the set points too wide?

How were the set points determined?

Sampling

How do I sample?

What do I sample?

Where do I sample?

Why should I sample?

How much sample should I take?

What does the data mean after it is obtained?

Final Product

How were the specifications set?

Are the tests reliable?

Creating a Master Validation Plan

By : Sami Power

You might be wondering what master validation plan is and how to create one for your organization. This article can help you understanding the principle of master validation plan and what is involved in creating one.

If you are in pharmaceutical business you have already noticed that you need a validation plan for qualifying your equipments, processes, cleaning systems, buildings and facilities. It is a regulatory requirement for you to create one and implement in your site. If you are to make your product safe, pure, effective and identifiable at all times for human use, you definitely need to create an effective MVP.

An effort to define master validation plan (MVP):
MVP is a strategic document which identifies the elements to be validated, the approach to be taken for validation of each element, the organizational responsibilities and the documentation to be produced in order to ensure full consideration is given to product quality aspects. It will show how the separate validation activities are organized and inter-linked. Overall it provides the details and relative timescales for the validation work to be performed.

You have to create standard operating procedures for the preparation of validation documents which are approved by the Quality Assurance.

When does a MVP required:
A MVP is needed when significant changes are made to the facilities, the equipment and processes which may affect the quality of the product. A risk assessment approach should be used to determine the scope and extent of validation. The MVP should be available prior to starting any of the validation activities

What should a MVP contains?
Each MVP shall describe the scope of the activities and address relevant key elements of validation affected by the change, indicating the actions and documents that will be needed. The key elements are those factors that can have an effect on product quality.

The content of the MVP should reflect the complexity of the extent of the validation activities to be undertaken. At minimum the MVP should address the following:

1. Title, statement of commitment and approval page.
2. Summary description of the project and its scope.
3. A statement of validation policy and the objectives of the validation activity
4. References to other existing validation documents.
5. A description of the organization and responsibilities for validation
6. The validation strategy to be adopted opposite Facilities and Systems (process equipment and services including automated systems), Materials, Quality Control, Personnel including training.
7. The intent in respect of Process Validation and Cleaning Validation for each of the drug product range.
8. The documentation management and control system to be used.
9. A description of the validation change management process.
10. An indicative relative timescale plan.
11. Clear acceptance criteria against which the outcome of the validation exercise will be judged.

Reporting requirement for master validation plan:
Each MVP should result in a report confirming that all validation activities have been completed satisfactorily.

It is recommended that a Summary Validation Report (or Master Validation Report) is prepared which summarizes activities undertaken, presents the overall conclusions and provides cross references to any associated reports or follow up actions.

Laboratory Equipment Qualification

The main goal in qualifying laboratory equipment is to ensure the validity of data.The current equipment qualification programs and procedures used within the pharmaceutical industry are based o­n regulatory requirements, voluntary standards, vendor practices, and industry practices.The result is considerable variation in the way pharmaceutical companies approach the qualification of laboratory equipment and the way they interpret the often vague requirements.The authors summarize the conclusions of the PhRMA Workshop o­n Acceptable Analytical Practices for the topic “Qualification of Laboratory Equipment.” They describe the areas ofagreement and offer options for areas in which there is variation o­n what is appropriate.

For full article Click Here

Author(s):
Kenneth W. Sigvardson, Joseph A. Manalo,Robert W. Roller, Fatieh Saless, and David Wasserman.

Showing newest posts with label Validation. Show older posts Control of Quality Records in the Pharmaceutical Industry

By : Jean White
Pharmaceutical Technology Europe

As in so many disciplines, the theory is much easier to accept than the practice. Before the task of maintaining document security becomes too overwhelming or shamefully neglected, it is prudent - and will save time and later frustration - to look at the number and nature of records involved. For the pharmaceutical industry (and companies embarking on ISO9000:2000 quality system development), all documents included in the processes of contract management, statutes, regulation, jurisdiction, purchasing (approved supplier records), receiving and shipping, design and development, production and administration (where applicable) are classed as "quality records" and "critical." The documents involved in the needs of any other interested parties (particularly customers) should also be considered.

The control and security of documents is more manageable if distribution is limited to those who "need to know." This means setting out the criteria for distribution at a very early stage in design and production development. Hard copy and electronic documents must be available for use where and when they are most needed. Every aspect of development and production, and the people involved in the process, must be considered carefully to ensure that everyone has the information they need, when they need it.

Creating a master document list
The main task will be to create a master document list that will record, in hard copy or electronically, all the documents involved - from contract review to final delivery of the product. The following questions must be asked at the first contract review stage:

- Is the document critical or non-critical?
- Who will control the list? (Preferably limited to one authorized individual.)
- Who will have authorized access for review, revision and amendment? (Usually the quality assurance manager, but in larger companies it could be the technical library staff or engineering staff.)
- Who should be considered when compiling the list of "authorized, responsible individuals"? Any persons responsible for review and release must be identified and their names and responsibilities circulated to other listed authorities. Keep a "signatories list" to safeguard against, and identify, the squiggles that some people use as signatures.
- Have the documents been subjected to the severest scrutiny before issue? Verification of content, a logical sequence of events with the reader in mind, grammar and spelling (particularly for international markets) should all be addressed.
- Are the documents clearly written with the reader in mind?
- Where do the documents begin to appear in the design and production process?
- Do they include user documents?
- What is the distribution? (Please, no uncontrolled copies!)
- What are the intradepartmental connections for each document and how are other agencies involved?
- Where will the documents be kept? (Secure from damage or other deterioration such as climate.)
- Who will be in charge of the documents at the point of use?
- Has documentation development been included in the quality plan and management quality objectives?

User publications are sometimes given short shrift in the development plans. Given their rightful place in the development process, questions will be asked such as: does the author need to know the product? At which stage should the author(s) be brought into the process? The answer is, the earlier the better: in fact, as soon as the design process is under way or even at the design note stage.

You may be under the impression that the above concerns are known and understood by all senior company executives, who govern themselves accordingly; unfortunately, they do not. I have seen files of critical documents stored in the most lamentable conditions, subject to the onslaught of seagulls. This is less likely to happen nowadays, with documents stored electronically. Many companies, however, simply update documents and put the latest version online at prescribed (or ad hoc) intervals, consigning previous versions to the waste basket. In some circumstances, the history and revision trail of the document can be preserved if the previous revisions have been exported to another authorized individual within the company, but this process can weaken the security of documents.

Password protection Given the many constraints surrounding the protection of our documents, many of us place great trust in our passwords. Unfortunately, as Steve Hughes, managing director of DLP Consulting, points out: "The flaws existing in current password application could lead to serious breaches of security. You can bypass password dialogue boxes in older Windows operating systems (pre-Win2000/XP)." He observes further that: "Although safeguards are available that include software for fingerprint recognition, encoding and encrypting documents, encoding and encrypting e-mail when it constitutes a part of the quality system, many files are not password-protected at document level. Time- and date-stamping on database records (for example, financial and testing records) could protect documents from unauthorized interference."

Legal implications In addition to the strictures expressed in the US Food and Drug Administration (FDA) standards, the legal implication of electronic data transfer has become a thorny issue. Publications such as The Legal Admissibility and Evidential Weight of Information Stored Electronically (BSI), although informative, simply add to our fears that we are becoming more and more embroiled in unmanageable requirements.

Best practice The remedy is to follow best practice wherever possible. This does make sense when you think of the pharmaceutical industry as being (like the aerospace industry) an unforgiving environment for error and where traceability is a critical factor in design and product development. The same security procedures that are used in the financial systems controlling life assurance, pensions and banking can apply, where the recording of transaction dates and times are vital and bespoke systems are built to ensure this protection. You can also

- protect the backup tape (make sure it doesn't fall into the wrong hands)
- lock the server room
- install a firewall to stop Internet hacking
- pay attention to LAN security
- have a procedure for signing off and make sure everyone follows it
- vet staff before assigning passwords and other authorization to them

As well as all the above precautions, I would like to think that you are paying close attention to the style and content of the documents. Clarity is essential; try to stay away from "management speak" and other faddy language that can clutter the best thought-out and well-intentioned policies and procedures.

The main thing is to start the document control process in small, manageable pieces. You can create categories for the master document list from components of standards such as ISO9000:2000, which cover every aspect of a quality system. This will ensure that you have included all possible document sources.

Remember to assign the relevant authorities and responsibilities at the earliest possible stage in the project. Nothing will create more confusion than a last minute attempt to assess and categorize documents. Document control is the number one cause of failure in assessment for ISO9000:2000, and the component which, if neglected, will cause the greatest difficulties. You don't want this to happen in your company, do you?

Concept of Process Validation For Pharmaceutical Industry

By : Sami Power

According to GMP definition Validation is "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."

Appropriate and complete documentation is recognized as being crucial to the validation effort. Standard Operating Procedures (SOPs), manufacturing formulae, detailed batch documentation, change control systems, investigational reporting systems, analytical documentation, development reports, validation protocols and reports are integral components of the validation philosophy. The validation documentation provides a source of information for the ongoing operation of the facility and is a resource that is used in subsequent process development or modification activities.

All validation activities will incorporate a level of Impact Assessment to ensure that systems, services and products directly influenced by the testing have been identified.

A revalidation program should be implemented based on routine equipment revalidation requirements and on the Change Control Policy.

Types of Validation

Prospective validation
Establishing documented evidence that a piece of equipment/process or system will do what it purports to do, based upon a pre-planned series of scientific tests as defined in the Validation Plan.

Concurrent validation
Is employed when an existing process can be shown to be in a state of control by applying tests on samples at strategic points throughout a process; and at the end of the process. All data is collected concurrently with the implementation of the process until sufficient information is available to demonstrate process reproducibility.

Retrospective validation
Establishing documented evidence that a process does what it purports to do, based on review and analysis of historical data.

Design Qualification (DQ)
The intent of the DQ is met during the design and commissioning process by a number of mechanisms, which include:

- Generation of User Requirement Specifications
- Verification that design meets relevant user requirement specifications.
- Supplier Assessment /Audits
- Challenge of the design by GMP review audits
- Product Quality Impact Assessment
- Specifying Validation documentation requirements from equipment suppliers
- Agreement with suppliers on the performance objectives
- Factory Acceptance Testing (FAT), Site Acceptance Testing (SAT) & commissioning procedures
- Defining construction and installation documentation to assist with Installation Qualification (IQ).

Installation Qualification (IQ)
IQ provides documented evidence that the equipment or system has been developed, supplied and installed in accordance with design drawings, the supplier's recommendations and In-house requirements. Furthermore, IQ ensures that a record of the principal features of the equipment or system, as installed, is available and that it is supported by sufficient adequate documentation to enable satisfactory operation, maintenance and change control to be implemented.

Operational Qualification (OQ)
OQ provides documented evidence that the equipment operates as intended throughout the specified design, operational or approved acceptance range of the equipment, as applicable. In cases where process steps are tested, a suitable placebo batch will be used to demonstrate equipment functionality.
All new equipment should be fully commissioned prior to commencing OQ to ensure that as a minimum the equipment is safe to operate, all mechanical assembly and pre-qualification checks have been completed, that the equipment is fully functional and that documentation is complete.

Performance Qualification (PQ)
The purpose of PQ is to provide documented evidence that the equipment can consistently achieve and maintain its performance specifications over a prolonged operating period at a defined operating point to produce a product of pre-determined quality. The performance specification will reference process parameters, in-process and product specifications. PQ requires three product batches to meet all acceptance criteria for in-process and product testing. For utility systems, PQ requires the utility medium to meet all specifications over a prolonged sampling period.

The PQ documentation should reference standard manufacturing procedures and batch records and describe the methodology of sampling and testing to be used.

What Gets Validated
General
All process steps, production equipment, systems and environment, directly used for the manufacture of sterile and non sterile products must be formally validated.

All major packaging equipment and processes should be validated. This validation is less comprehensive.
All ancillary systems that do not directly impact on product quality should be qualified by means of a technical documentation of the extent of the system and how it operates.

Facility
- Manufacturing Area Design.
- Personnel and material flow etc.

Process and Equipment Design
Process steps and equipment description. i.e. Dispensing, Formulating, Packaging, Equipment washing
and cleaning. etc

Utility Systems Design
Raw/purified steam, Purified water, Compressed Air, Air conditioning system, Vacuum, Power supply, Lighting, Cooling water, Waste etc

Computerized Systems Design
Information system, Laboratory automated equipments, Manufacturing automated equipments, Electronic records etc

Cleaning Validation (CV)
CV provides documented evidence that a cleaning procedure is effective in reducing to pre-defined maximum allowable limits, all chemical and microbiological contamination from an item of equipment or a manufacturing area following processing. The means of evaluating the effectiveness of cleaning involves sampling cleaned and sanitized surfaces and verifying the level of product residues, cleaning residues and bacterial contamination.

The term CV is to be used to describe the analytical investigation of a cleaning procedure or cycle. The validation protocols should reference background documentation relating to the rationale for "worst case" testing, where this is proposed. It should also explain the development of the acceptance criteria, including chemical and microbial specifications, limits of detection and the selection of sampling methods.

Method Validation (MV)
MV provides documented evidence that internally developed test methods are accurate, robust, effective, reproducible and repeatable. The validation protocols should reference background documentation relating to the rationale for the determination of limits of detection and method sensitivity.

Computer Validation
Computer Validation provides documented evidence to assure systems will consistently function according to their pre-determined specifications and quality attributes, throughout their lifecycle. Important aspects of this validation approach are the formal management of design (through a specification process); system-quality (through systematic review and testing); risk (through identification and assessment of novelty and critical functionality) and lifecycle (through sustained change control).

Where equipment is controlled by embedded computer systems, elements of computer validation may be performed as part of the equipment IQ and OQ protocols.