Auditing Process Validation

Thursday, December 31, 2009

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?

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.

Quality by Design Streamlines Pharmaceutical Manufacturing

By : Norm Howe

The pharmaceutical industry wastes more than $50 billion a year in manufacturing costs, this according to findings of a study on the interplay of pharmaceutical manufacturing and the Food and Drug Administration (FDA). The study, conducted jointly by Olin School of Business at Washington University and McDonough School of Business at Georgetown University, received no funding from either the pharmaceutical industry or the FDA.

The goal of the study was to understand how the FDA regulates pharmaceutical production and how those regulations may be inhibiting advances in manufacturing. The study looked at data collected from 42 manufacturing facilities owned by 19 manufacturers, in particular each company?s manufacturing performance in terms of cycle time, frequency of deviations, reasons for deviations, yield, and improvement rates on key manufacturing metrics.

The outcome identified two factors that could be assisted by Quality-by-Design. First, companies using information technology to electronically track and report on manufacturing and centrally stored all their data displayed superior manufacturing performance relative to those not using such information technology. Second, the ability of employees in lower ranks to make decisions directly correlated to gains in manufacturing performance, particularly regarding deviation management, lot failure, lot review and process validation.

The FDA?s Quality by Design (QbD) initiative has shifted quality control from a static end result to an ongoing, evolving entity?one that tracks a product from inception to creation, rather than looks only at the final product. The QbD initiative, which originated from the Office of Biotechnology Products (OBP), attempts to provide guidance on pharmaceutical development to facilitate design of products and processes that maximizes the product?s efficacy and safety profile while enhancing product manufacturability.

Fundamental to this initiative is the understanding of the relationship between the quality attributes of the product (physicochemical and biological properties) and their impact on the safety and efficacy. This requires knowledge of the relationship between structure and biological functions.

In short, QbD is a scientific, risk-based, holistic and proactive approach to pharmaceutical development, as well as deliberate design effort from product conception through commercialization. QbD offers a full understanding of how product attributes and process relate to product performance.

The initiative benefits everyone by ensuring better design of products with less problems in manufacturing. It also reduces the number of manufacturing supplements required for post market changes, and allows for implementation of new technology to improve manufacturing without regulatory scrutiny, as well as possible reduction in overall costs of manufacturing.

QbD ensures reduced deficiencies, quicker approvals, and improved interaction with FDA. It also allows for continuous improvements in products and manufacturing process, as well as a better understanding of how APIs and excipients affect manufacturing. Lastly, it relates manufacturing to clinical during design, and provides a better overall business model.

FDA Approves a High Dose Seasonal Influenza Vaccine Specifically Intended for People Ages 65 and Older

Sunday, December 27, 2009

The U.S. Food and Drug Administration today approved Fluzone High-Dose, an inactivated influenza virus vaccine for people ages 65 years and older to prevent disease caused by influenza virus subtypes A and B.

People in this age group are at highest risk for seasonal influenza complications, which may result in hospitalization and death. Annual vaccination remains the best protection from influenza, particularly for people 65 and older.

Fluzone High-Dose was approved via the accelerated approval pathway. FDA’s accelerated approval pathway helps safe and effective medical products for serious or life-threatening diseases become available sooner. In clinical studies, Fluzone High-Dose demonstrated an enhanced immune response compared with Fluzone in individuals 65 and older.

As part of the accelerated approval process, the manufacturer is required to conduct further studies to verify that the Fluzone High-Dose will decrease seasonal influenza disease after vaccination.

"As people grow older, their immune systems typically become weaker," said Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research. "This is the first influenza vaccine that uses a higher dose to induce a stronger immune response that is intended to better protect the elderly against seasonal influenza."

Fluzone High-Dose, manufactured by Sanofi Pasteur Inc., is formulated so that each 0.5 mL dose contains a total of 180 micrograms (mcg) of influenza virus hemagglutinin (HA) which is made up of 60 mcg of each of the three influenza virus strains.

Other currently licensed seasonal influenza vaccines for adults are formulated to contain a total of 45 mcg of influenza virus hemagglutinin (15 mcg HA from each of the three influenza strains per dose). Sanofi Pasteur, also manufactures Fluzone, a seasonal vaccine for the United States approved for use in individuals ages 6 months and older.

As expected, because of the higher HA content, non-serious adverse events were more frequent after vaccination with Fluzone High-Dose compared with Fluzone. Common adverse events experienced during clinical studies included pain, redness and swelling at the injection site and headache, muscle aches, fever and malaise. The rate of serious adverse events was comparable between Fluzone High-Dose and Fluzone.

People with hypersensitivity to egg proteins or life-threatening reactions after previous administration of any influenza vaccine should not be vaccinated with Fluzone High-Dose.

Fluzone High-Dose is administered as a single injection in the upper arm and is available in single dose pre-filled syringes without preservative.

Does GMP Compliance Mean A Quality Assurance Process Providing High Quality Supplements?

By : Wanda McCormick

Fact… 45% of all supplements you buy are defective in some way. Will the GMP change that?

Until now there have been no laws requiring the label to accurately tell you what is actually in your bottle of vitamins or supplements. So the government has begun requiring certification programs that must be verified by an independent lab on all supplements and vitamins. The GMP or Good Manufacturing Practice certification will begin in 2009. This verifies quality control, cleanliness, checking the identity and potency of ingredients, and testing of the final products for potency, purity and authenticity.

There will be plant inspections to observe cleanliness. This was implemented due to truly filthy conditions observed in equipment used to process and bottle supplements. I saw a picture of one that was processing a powder with cob webs actually inside the machine’s duct work and powder everywhere, on the floor, handles and knobs. If the powder could get out so easily and spiders could get in, then what insects etc were actually in the powder?

Testing will be done on raw materials coming into the plant. This is due to so many instances of products coming from overseas that were not what they were supposed to be. In order to make more money the products were “cut” with other less expensive ingredients. In one instance China companies added Melamine to baby formula. Melamine is used to make the plastic place settings you see in department stores. 13,000 children were hospitalized after drinking the tainted baby formula. 22 companies were involved and the contaminated formula had been sold all over the world. Chinese parents were in a panic not knowing what was safe to feed their infants. Other examples of contaminants include heavy metals foune in 25% of products coming from both India and China. What makes this so dangerous is that manufacturers are buying “boat loads”, literally, of product and just putting them into capsules without any product testing. Whatever is in the imported powder goes right into your capsules.

Then there will also be testing of the final product for potency, purity, and authenticity. Potency just means that the amount listed on the label is actually the amount in the bottle. For example is there really 500 mg of Vitamin C in each pill? Many times the making of the finished product uses heat which destroys some of the potency, but the label lists the original potency of the raw product.

Let me give you an example, whey protein comes from milk. One way it is taken out of the milk keeps just about all the whey protein undamaged. Another way to remove whey involves heat which is a cheaper process. It keeps the cost down, but destroys some of the protein. Labels will now be required to reflect this difference in potency. Purity means that the final product contains no contaminants, like heavy metals, insect parts or melamine.

Authenticity means that the final product is what it says it is, that a bottle of calcium really is calcium. Until now 10% of what you buy on the shelf doesn’t even have the main, active, ingredient in it. Sometimes it is just a powder or pill that looks like the real thing. One of the articles I read talked about a companies problems with it’s product. It was not what it was supposed to be. It turned out the independent lab that was doing the testing for the manufacturer was using “visual testing” to tell if the product was pure or not. This entailed putting a special wavelength of light on the powder and if the product glowed then it was considered pure and authentic. What they didn’t take into consideration was that other powders also glow under that same light. While this was a cheaper test that helped to keep cost low, it did not do what it was supposed to do! While the more expensive chemical testing easily showed the product had been "cut" with something else and was not pure or authentic.

The upside to all this is obvious, that we will “really” get what we are paying for. It will provide the real health benefit it is supposed to and it won’t make us sick from contaminates. But there is a down side. Foreign suppliers will have to export the real thing or we won’t buy it. With all the super cheap products no longer available, the demand and the price for the real thing will go up. Also manufacturers will have to replace outdated equipment, set up quality controls and in-house testing or hire independent labs. Some will not be able to afford the updates and will go out of business. Even if the manufacturers are able to upgrade, they will still have to pass government testing in order to be certified and some will just not pass. Those manufacturers that do survive will see a higher demand for their products, which will generate more sales to offset the added costs, but most likely will still pass the increased cost along to us, making our supplements cost more.

The silver lining is that there are manufactures out there that already do all this and won’t be effected,and have always given us the best possible products. Now everyone will know who they are. Sometime in 2009 you will start to see symbols on the certified products testifying to their quality. Look for the GMP stamp of approval. You can see some of the symbols on my website at http://thebestproteinshakes.com/numbers-dont-tell-it-all/ and Dr Kones who helped me write this article has volunteered to answer any questions about nutrition you might have. His email address is on the same page as the Certification Symbols.

My site discusses Protein powders and how much they vary, so it is crucial to know what's in them. It's http://www.thebestproteinshakes.com/. Visit and let me help you compare the different types of protein powders. It shows how to read and understand the labels. Then it helps you sift through it all to find the best protein for you.