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.


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.


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


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?


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?


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

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
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.

- 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.

Definations and brife explanations for pharmacy studants

In pharmaceutical manufacturing industry Validation is very important part of Quality assurance and in Good manufacturing Practice activities or guidelines .FDA gives special emphasis on validation , also it is one of the prime requirement of all regulatory authorities world wide. It is of great importance in Pharmaceutical manufacturing as well as medical devices manufacturing industry.
Validation is a process of collection of documentary evidence , it is a process of demonstration that any of the procedure, process, method, or activity is being adapted is capable of producing consistant and satisfactory result in terms of measurements or in terms of product quality.

To demonstrate this it is required that the systems it slef and equipment are properly designed and qualified. To demonstrate that a pharmaceutical product manufactured with any process in any pharmaceutical company it is required to validate many procedures, processes, methods activities associated with pharmaceutical manufacturing including machinery , skills and testing procedures , methods.
Validation In pharmaceutical is classified as follows
1.Cleaning Validation
2.Process Validation
3.Analytical Method Validation
4.Computer System Validation

And qualifying systems ,equipments are required to qualify for following Qualifications:
1.Design qualification (DQ)
2.Component qualification (CQ)
3.Installation qualification (IQ)
4.Operational qualification (OQ)
5.Process qualification (PQ)

Design Qualification (DQ)- It consists process of gathering documentary evidence of a particular instruments or machine’s fundamental operational and functional specification of an instrument , and its inherent program , or equipment and details about and its detailed design and its qualifications , why this instrument and is supplier chosen.

Installation Qualification (IQ) - It consists process of gathering documentary evidence and process of Demonstration that the process or equipment being installed complies with all of its qualifications of successful installation in a particular aria , so as to comply with intended requiremts of process , with respect to its specifications, is it installed correctly, are all necessary accessories and components installed correctly and its documentation required for continued utilization are installed properly.

Operational Qualification (OQ) - It consists process of gathering documentary evidence and of Demonstration of all aspects of a equipment , process are functioning properly and accurately so as to yield intended ,mesurments, results quality of a pharmaceutical being manufactured.

Performance Qualification (PQ) - It consists process of gathering documentary evidence and process of Demonstration of all aspects of a equipment , process are functioning properly and accurately so as to produce intended ,mesurments, results , intended quality of a pharmaceutical manufactured over a period of time. in a consistent manner

Validation Master Plan
It is a document which identifies and provides complete steps, guide or map or guidelines for caring out a particular validation procedure.
Where ever there is requirement of any validation , Validation procedure is first asiged a Validation Master Plan.

The Validation Process
It is a process of monitoring ,testing,and evaluation of all steps and process involved in a pharmaceutical manufacturing
Computer system Validation:
It requires that the software or programs which are utilized by pharmaceutical companies in manufacturing of pharmaceuticals should work without any error, it provides or leads to an accurate measures or activity .Example Dispensing of Raw Material using computarised system. Process control using a computarised system
In 21 CFR Part 11 this topic is covered in very detail and you can read it over here
Here screen shot prints are gathered to validate and document that the procedure adapted is leads to correct measures or activity

Validation of Aseptic Process and Sterilisation

Media Fill Run to ensure the sterility Sterile dosage form evaluation of manufacturing process by Process Simulations /media fill run

Validation of sterile dosage form manufacturing is devided in to three parts
A. Process Simulations :
B. Filtration Efficacy.
C. Sterilization of Equipment, Containers, and Closures :

Filtration Efficacy and Sterilization of Equipment, Containers, and Closures are allready disscused.

In this article we will be focused on ( A. Process Simulations , ie.Media fill run)

We have answered following important regularly asked questions about media fill run.

1.Media Fill Study Design
2.Specific provisions in written procedures relating to aseptic processing
3. Duration of Media Fill Runs
5. Line Speed during media fill run
6. Environmental Conditions
7.Microbilogical Enrichment Media for Media Fill
8. Incubation and Examination of Media-Filled Units
9. Interpretation of Test Results in media fill run
10.Evaluation of state of aseptic line control

Apart from this article we have provided more information about media fill find it over here

We have provided answere to your question , if media fill run fails , a case study

-----------------------------------------------------------------------------------------------------------To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling and closing operations must be adequately validated (CFR 211.113). The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug formulation, the container, and the closure) are brought together under conditions that contaminate any of those elements.

An aseptic processing operation should be validated using a microbiological growth medium in place of the product. This process simulation, also known as a media fill, normally includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo. The sealed containers filled with the medium are then incubated to detect microbial contamination. Results are then interpreted to assess the potential for a unit of drug product to become contaminated during actual operations (e.g., start-up, sterile ingredient additions, aseptic connections, filling, closing). Environmental monitoring data from the process simulation can also provide useful information for the processing line evaluation.

1. Study Design

A media fill program should incorporate the contamination risk factors that occur on a production line, and accurately assesses the state of process control. Media fill studies should closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations.

FDA recommends that the media fill program address applicable issues such as:

1. Factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue)
3. Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments)
4. Lyophilization, when applicable
5. Aseptic assembly of equipment (e.g., at start-up, during processing)
6. Number of personnel and their activities
7. Representative number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients) or transfers
8. Shift changes, breaks, and gown changes (when applicable)
9. Type of aseptic equipment disconnections/connections
10. Aseptic sample collections
11. Line speed and configuration
12.Weight checks
13. Container closure systems (e.g., sizes, type, compatibility with equipment)

2.Specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted before line clearance is mandated)

A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks.

A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks.(One example might be the movement of personnel into and out of the aseptic processing and gowning change rooms during a shift change.)
All personnel who are authorized to enter the aseptic processing room during manufacturing, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator’s duties during routine production.

Each change to a product or line change should be evaluated using a written change control system. Any changes or events that have the potential to affect the ability of the aseptic process to exclude contamination from the sterilized product should be assessed through additional media fills. For example, facility and equipment modifications, line configuration changes, significant changes in personnel, anomalies in environmental testing results, container closure system changes, extended shutdowns, or end product sterility testing showing contaminated products may be cause for revalidation of the system.

When data from a media fill indicate the process may not be in control, an investigation should be conducted to determine the origin of the contamination and the scope of the problem. Once corrections are instituted, process simulation run(s) should be performed to confirm that deficiencies have been corrected and the process has returned to a state of control. When an investigation fails to reach well-supported, substantive conclusions as to the cause of the media fill failure, three consecutive successful runs in tandem with increased scrutiny of the production process may be warranted.

3. Duration of Runs

The duration of aseptic processing operations is a major consideration in media fill design. Although the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production operations, other appropriate models can be justified. The duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions, as well as appropriate consideration of the duration of the actual aseptic processing operation. Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically.

While conventional manufacturing lines are usually automated, operated at relatively high speeds, and designed to limit operator intervention, some processes still include considerable operator involvement. When aseptic processing employs manual filling or closing, or extensive manual manipulations, the duration of the process simulation should generally be no less than the length of the actual manufacturing process to best simulate contamination risks posed by operators.

For lyophilization operations, FDA recommends that unsealed containers be exposed to partial evacuation of the chamber in a manner that simulates the process. Vials should not be frozen, and precautions should be taken that ensure that the medium remains in an aerobic state to avoid potentially inhibiting the growth of microorganisms.

4. Size of Runs

The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination. The number of units filled during the process simulation should be based on contamination risk for a given process and sufficient to accurately simulate activities that are representative of the manufacturing process. A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units. For operations with production sizes under 5,000, the number of media filled units should at least equal the maximum batch size made on the processing line.

When the possibility of contamination is higher based on the process design (e.g., manually intensive filling lines), a larger number of units, generally at or approaching the full production batch size, should be used. In contrast, a process conducted in an isolator can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation.

Media fill size is an especially important consideration because some batches are produced over multiple shifts or yield an unusually large number of units. These factors should be carefully evaluated when designing the simulation to adequately encompass conditions and any potential risks associated with the larger operation.

5. Line Speed

The media fill program should adequately address the range of line speeds employed during production. Each media fill run should evaluate a single line speed, and the speed chosen should be justified. For example, use of high line speed is often most appropriate in the evaluation of manufacturing processes characterized by frequent interventions or a significant degree of manual manipulation. Use of slow line speed is generally appropriate for evaluating manufacturing processes with prolonged exposure of the sterile drug product and containers/closures in the aseptic area.

6. Environmental Conditions

Media fills should be adequately representative of the conditions under which actual manufacturing operations are conducted. An inaccurate assessment (making the process appear cleaner than it actually is) can result from conducting a media fill under extraordinary air particulate and microbial quality, or under production controls and precautions taken in preparation for the media fill. To the extent standard operating procedures permit stressful conditions (e.g., maximum number of personnel present and elevated activity level), it is important that media fills include analogous challenges to support the validity of these studies. Stressful conditions do not include artificially created environmental extremes, such as reconfiguration of HVAC systems to operate at worst-case limits.

7. Media

In general, a microbiological growth medium, such as soybean casein digest medium, should be used. Use of anaerobic growth media (e.g., fluid thioglycollate medium) should be considered in special circumstances. The media selected should be demonstrated to promote growth of gram-positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms). The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates. Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge. Growth promotion units should be inoculated with a <100>8. Incubation and Examination of Media-Filled Units

Media units should be incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture. Incubation conditions should be established in accord with the following general guidelines:

1. Incubation temperature should be suitable for recovery of bioburden and environmental isolates and should at no time be outside the range of 20-35oC. Incubation temperature should be maintained within +2.5oC of the target temperature.

2.Incubation time should not be less than 14 days. If two temperatures are used for the incubation of the media filled units, the units should be incubated for at least 7 days at each temperature (starting with the lower temperature).

Each media-filled unit should be examined for contamination by personnel with appropriate education, training, and experience in inspecting media fill units for microbiological contamination. If QC personnel do not perform the inspection, there should be QC unit oversight throughout any such examination. All suspect units identified during the examination should be brought to the immediate attention of the QC microbiologist. To allow for visual detection of microbial growth, we recommend substituting clear containers (with otherwise identical physical properties) for amber or other opaque containers. If appropriate, other methods can also be considered to ensure visual detection.

When a firm performs a final product inspection of units immediately following the media fill run, all integral units should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected. Erroneously rejected units should be returned promptly for incubation with the media fill lot.

After incubation is underway, any unit found to be damaged should be included in the data for the media fill run, because the units can be representative of drug product released to the market. Any decision to exclude such incubated units (i.e., non-integral) from the final run tally should be fully justified and the deviation explained in the media fill report. If a correlation emerges between difficult to detect damage and microbial contamination, a thorough investigation should be conducted to determine its cause
Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention type; quantity of units removed), providing for consistent production practices and assessment of these practices during media fills. If written procedures and batch documentation are adequate to describe an associated clearance, the intervention units removed during media fills do not need to be incubated.(To assess contamination risks during initial aseptic setup (before fill), valuable information can be obtained by incubating all such units that may be normally removed. These units are typically incubated separately, and would not necessarily be included in the acceptance criteria for the media fill.
Where procedures lack specificity, there would be insufficient justification for exclusion of units removed during an intervention from incubation. For example, if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure. In no case should more units be removed during a media fill intervention than would be cleared during a production run.
The ability of a media fill run to detect potential contamination from a given simulated activity should not be compromised by a large-scale line clearance. We recommend incorporating appropriate study provisions to avoid and address a large line clearance that results in the removal of a unit possibly contaminated during an unrelated event or intervention.
Appropriate criteria should be established for yield (Total units incubated/total number of units filled.) and accountability (reconciliation of filled units). Media fill record reconciliation documentation should include a full accounting and description of units rejected from a batch.

9. Interpretation of Test Results

The process simulation run should be observed by the QC Unit, and contaminated units should be reconcilable with the approximate time and the activity being simulated during the media fill. Video recording of a media fill may serve as a useful aide in identifying personnel practices that could negatively affect the aseptic process.
Any contaminated unit should be considered objectionable and investigated. The microorganisms should be identified to species level. The investigation should survey the possible causes of contamination. In addition, any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill.
Whenever contamination exists in a media fill run, it should be considered indicative of a potential sterility assurance problem, regardless of run size. The number of contaminated units should not be expected to increase in a directly proportional manner with the number of vials in the media fill run. Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile. Modern aseptic processing operations in suitably designed facilities have demonstrated a capability of meeting contamination levels approaching zero and should normally yield no media fill contamination.
Recommended criteria for assessing state of aseptic line control are as follows:
1. When filling fewer than 5000 units, no contaminated units should be detected. -- One (1) contaminated unit is considered cause for revalidation, following an investigation.

2. When filling from 5,000 to 10,000 units: -- One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill. -- Two (2) contaminated units are considered cause for revalidation, following investigation.

3.When filling more than 10,000 units: -- One (1) contaminated unit should result in an investigation. -- Two (2) contaminated units are considered cause for revalidation, following investigation.
For any run size, intermittent incidents of microbial contamination in media filled runs can be indicative of a persistent low-level contamination problem that should be investigated.

Accordingly, recurring incidents of contaminated units in media fills for an individual line, regardless of acceptance criteria, would be a signal of an adverse trend on the aseptic processing line that should lead to problem identification, correction, and revalidation.

A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit. The purpose of an aseptic process is to prevent any contamination. A manufacturer is fully liable for the shipment of any nonsterile unit, an act that is prohibited under the FD&C Act (Section 301(a) 21 U.S.C. 331(a)). US FDA also recognizes that there might be some scientific and technical limitations on how precisely and accurately process simulations can characterize a system of controls intended to exclude contamination.
As with any process validation run, it is important to note that invalidation of a media fill run should be a rare occurrence. A media fill run should be aborted only under circumstances in which written procedures require commercial lots to be equally handled. Supporting documentation and justification should be provided in such cases.



Manufacturers should build process and environmental control activities into their aseptic processing operation. It is critical that these activities be maintained and strictly implemented on a daily basis. The requirement for review of all batch records and data for conformance with written procedures, operating parameters, and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211.188. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are considered essential elements of the batch release decision.

While interventions and/or stoppages are normally recorded in the batch record, the manner of documenting these occurrences varies. In particular, line stoppages and any unplanned interventions should be sufficiently documented in batch records with the associated time and duration of the event. In addition to lengthened dwell time of sterile product elements in the critical area, an extensive intervention can increase contamination risk. Sterility failures have often been attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process. Written procedures describing the need for line clearances in the event of certain interventions, such as machine adjustments and any repairs, should be established. Such interventions should be documented with more detail than minor events. Interventions that result in substantial activity near exposed product or container closures or that last beyond a reasonable exposure time should, where appropriate, result in a local or full line clearance.

Any disruption in power supply, however momentary, that could affect product quality is a manufacturing deviation and must be included in batch records (CFR 211.100, 211.192).

Regulations pertaining to sterile pharmaceutical manufacturing , batch reveiw records

21 CFR 211.100(a) states that “There shall be 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. Such procedures shall include all requirements in this subpart. 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.”

21 CFR 211.100(b) states that “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.”

21 CFR 211.186 and 211.188 address, respectively, "Master production and control records" and "Batch production and control records."

21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.”