Why FDA Compliance Helps

Thursday, December 31, 2009

By : Mark Andrew Woodcock

FDA Compliance is an integral part of manufacture in the food, drug and cosmetic industries, to ensure that the public is not put at risk from consuming or using any new or sustained products on the market. There are several aspects of compliance including Good Manufacturing Practise, packaging and labelling, marketing and other factors. As an agency of the Department of Health and Human Services, the FDA is enabled to issue laws and enforce these on the 95,000 regulated businesses under its authority. The FDA ensures regulatory compliance across a number of products including food (excluding red meat and poultry), drugs, medical devices, blood, biological products, and cosmetics. The sole aim of FDA compliance is to safeguard the health of consumers and maintain the quality of products.

Only when organizations integrate FDA Compliance into their working lifestyle instead of viewing it as simply another regulation, will the authorities, businesses and consumers be happy.

There are two major impacts that failure to comply can have; public injury and company prosecution. When a product is contaminated, packaged incorrectly or fails to meet any of the regulations, consumers are put at risk, their health may suffer and in extreme cases, this can result in death. If the ingredients listed on packaging is incorrect, allergic reactions are possible, just as when the strengths are confused accidental overdoses may occur. For companies who fail to comply with the FDA, there are several possible outcomes, all of which are harmful to the longevity of the business. Product recall and seizure not only damages profits, but it also damages the stock of the business, making it less attractive to trade with and buyers are less likely to purchase products off them. For serious defiance of FDA compliance, a business can be fined huge sums of money and individual employees can be subject to criminal prosecution and jail sentences if they are found to have put human life at risk. The FDA publishes a list of companies and individuals who have been barred from working in any of the industries covered by the FDA due to criminal and life threatening activities. This alone should put compliance at the top of an organisation's agenda.

Whilst many businesses see compliance and regulation as a hindrance to their productivity and effectiveness, the FDA is working to make its regulations easier for manufacturers to adhere to and less like a drain on resources and employee focus. Many of the regulations are open ended and general which allows managers to implement them to suit their individual business. Smaller organisations will require a different approach than larger companies and the open-endedness reflects this.

FDA Compliance covers record keeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation and complaint handling. All of these features work towards public satisfaction and safety, keeping the quality of food, drugs, cosmetics and other products under FDA regulation high, whilst allowing businesses to work in ways which suit them. There would be no point in enforcing all of these regulations if productivity was hampered and research stifled. These regulations still allow for advances in science and technology, but they put public safety as their top priority.

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.

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?

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.

A Recommended Quality System Model With Management Software

By : Alberto Sanchez

In the pharmaceutical industry, it can be difficult to find a quality system model that provides a rendezvous point to conform with the FDA's cGMP initiative, 21 CFR Parts 210 and 211 regulations, the FDA's Critical Path Initiative, ISO 9000 standards, and the requirements of foreign regulatory bodies.

The FDA, however, has created a quality systems model in the Quality Systems Approach to Pharmaceutical cGMP Regulations guidance document that can show pharmaceutical companies a high-functioning system that will help meet all of those regulations. One of the categories the document focuses on is management responsibilities, and we will discuss those responsibilities and the possibility to automate many of the associated administrative tasks.

According to the FDA's Quality Systems Approach quality system model, senior management should demonstrate commitment to developing and maintaining the quality system. The development of a quality system takes time and dedication. No matter how much a manager may know about the complexities and the "ins and outs" of various quality system models, he or she will invariably need to commit to the development of the quality system itself.

Management should be responsible (to reasonable degree) in all aspects of quality system maintenance and will often be in charge of data analysis and subsequent decision making issues. However, managers often spend most of their energy on the early stages of the quality system which are usually nothing more than tedious administrative tasks. This is unfortunate since many of the stages of quality system maintenance are prime opportunities for automation.

Quality management personnel in regulated pharmaceutical environments can take advantage of "automation benefits" by using software solutions. In short, these solutions should provide the data and trending technology that makes it easy to identify quality system deviations and nonconformance events. With effective automation technology, important responsibilities of quality system maintenance are still managed but tedious administrative can be automated.

Another responsibility for managers is to ensure that quality system plans are always aligned with a manufacturer's strategic plans. A quality system-regardless of the type-is never an entity unto itself.

It really is part of everybody's business. That is why it is essential that the quality system plans of any pharmaceutical company meet with the goals and realities of other systems and processes that occur throughout the industry.

It can be difficult, however, to align quality system management with other processes and departments (even beyond manufacturing) because departments have a natural tendency to be disjointed and subjective. An automated process will allow pharmaceutical companies to essentially connect quality, compliance and everyday procedural processes with applications that are launched from one platform.

In the pharmaceutical industry, it sometimes seems that the facets of managerial responsibilities are innumerable. However, modern quality management solutions (GxP management solutions for instance) have been designed to consolidate and considerably ease the efforts required by pharmaceuticals management personnel.

A New Paradigm to Address the High Cost of Vendor Qualification

By : Norm Howe

When FDA inspected a Heparin supplier, Shanghai No. 1 Biochemical & Pharmaceutical Co. Ltd., they thought they were seeing the real plant. It turned out that it was only a show facility. The real plant was a shadow plant located somewhere else. The US-FDA Warning Letter later stated, "The inspection revealed that the facility was not manufacturing, and did not appear to have ever manufactured, Heparin Sodium USP (or heparin sodium) for the U.S. market."

This case is similar to Baxter Pharmaceutical's experience with their Heparin supplier in 2008. The result of that deception was that hundreds of patients suffered life-threatening reactions like severe hypotension, low blood pressure and over 80 people died.

As of today there are more than 150 wrongful death cases filed against Baxter. The cost of defending itself in those suits in legal fees and employee time will be high to say the least. Even if Baxter were to win those cases, they would lose. The effort of an integrated supplier compliance program now seems small in hindsight.

Could this happen to you? How do you protect the quality of your product? What are FDA's expectations for supplier qualification? The Heparin experience shows that even an extreme onsite inspection won't necessarily reveal severe quality problems. How does one confirm that the supplier plant that you are inspecting is actually the one that supplies your company?

Some things to watch for, according to FDA, include discrepancies in date (e.g., compare when the materials arrived versus when production and testing were done) and if the facility happens to be "renovating" or "not manufacturing the day" you are there for your audit. You have to see the product being manufactured in action. You can also ask to see batch records and other documentation as proof the factory is indeed operational.

Does this solve the Show and Shadow supplier danger? No. Clearly it's not a full solution. And the fact is there is no sure solution. It's very difficult to detect someone who is determined to commit fraud. You as a buyer need to be sure that you have located the actual production facility. Fortunately these instances are rare, and most suppliers at least try to produce a quality product.

But this incident shows how critical a supplier's quality program can be. The message is that even intensive on-site audits cannot find major vendor problems. 'Show and Shadow' is just an extreme example.

Although FDA's suggestions are certainly valuable, they and all the other responses to the increasing concerns over vendor quality all seem to say one thing: more intensive audits. More intensive audits, of course, mean higher costs. And as we have seen even an intensive audit isn't guaranteed to find all the problems at a supplier. The problem is that audits are only a snapshot; a surface skim at a point in time.

Any pharmaceutical or medical device plant is a very complex place. Unless you plan to take up residence at the vendor you have no chance to understand the true nature of these operations. And what company in today's cost-cutting climate has the resources to do that? Keep in mind that an audit costs more than what you pay for your auditors to investigate the vendor. The vendor has to spend their time escorting the auditors around, digging out records, and following up on action items. Guess who has to cover that cost. The assumption today is that a BETTER audit means a LONGER audit. There has to be another way.

What's needed is a new paradigm for vendor qualification; a tool that can drill deeply into the vendor's operation at low cost; something that can provide a more lasting measure of the vendor's performance than simply an audit.

To get to the solution we have to answer this question, why don't vendors always comply with the regulations. My answer, based on years of auditing and operations management, is that by far the most common reason is lack of knowledge of the regulations through-out the organization. I'm not talking here about a general understanding of requirements. I mean a deep Knowledge of the details of how to comply with the regulations - not just that the packaging room needs to be inspected before packaging operations begin; but that previous materials have been removed, packaging and labeling materials inspected, extraneous materials removed, documentation, etc.

Sure, there is generally someone in most vendor organizations who knows the regulations. But in poorly performing companies the attitude is often that regulatory compliance is up to the Quality Department.

My proposition is that once everyone in an organization KNOWS the regulations as they apply to their jobs, DOING the job right is straightforward. The biggest hurdle to overcome is disseminating detailed Knowledge of what needs to be done to all the employees.

How can one use this relationship to assist with the problem of supplier qualification? What if it were possible to objectively measure what all the employees of a supplier know about GMPs (Good Manufacturing Practices)? That deep Knowledge plus a broad snapshot of the supplier based on an audit will give you a strong measurement of the supplier's performance.

The next question is how does one measure that Knowledge. Knowledge is not so easily measured in an audit. You can check training records. Usually you will see who sat through what training class, or who was checked off as proficient in on-the-job training. There is rarely any indication of what people actually KNOW.

So how could we effectively measure the Knowledge of all of a supplier's employees? Well, technology gives us an edge today that didn't exist not too long ago. Computer Based Training provides a reliable, and relatively cheap way to assure that all employees have a minimum skill level. Online GMP courses train and test any employee who has access to the internet. Learning Management Systems track who knows what, and make the results easily visible to management.

If you as a customer insist that suppliers test their employees and provide you with verification that all their employees have passed their GMP courses, then you can have a high degree of confidence that the supplier has the Knowledge to make compliant products. You as a customer can have independent access to the training verification reports. When your auditors cross-check the training reports against the names on batch records, the vendor suddenly becomes completely transparent.

There's another advantage when everyone in an organization is passing the same tests, peer pressure. It's not easy for one person to bypass a GMP requirement when everyone around knows that it's the wrong thing to do.

Requiring your vendor to give their employees online, verified GMP training insures that they have a deep Knowledge of the regulations. This doesn't really cost any incremental money because this is something the vendor should be doing anyway. Combining the visibility of an online Computer Based Training system with an audit can make your supplier's quality program truly transparent.

Top Ten Qualities to Look for in an Online Pharmacy

By : Amadou Moustapha Sall

As you may have noted, there are thousands or even hundreds of thousands of websites selling pharmaceutical products or drugs. These are called ONLINE PHARMACIES or PHARMACIES ONLINE.

Can they be trusted? Are they safe?

Yes, in many cases but only if you are careful and exercise your due diligence: this is all the more necessary since the consequences of cheating with pharmaceutical products can be much more serious than, for example, being conned into buying a useless fiction ebook or piece of sofware.

It can even be literally a matter of life and death.

So, here are the top 10 qualities to look for in an online pharmacy.

Go through the list carefully, use it as a filter for all the online pharmacies you come across, and you'll be covered!

1. ADEQUATE PRODUCT INFORMATION: It should be absolutely honest, say what the product does, what it does not do, side effects, incompatibilities, even... possible after-effects etc..

2. QUALITY: FDA-approved prescription drugs. Storage, Processing, Shipping must be under full compliance with US and FDA Regulations

3/4. SAFETY, SECURITY: If possible it should be accredited by bodies such as the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) - "one of the most stringent and respected accrediting organizations dedicated to continuously improving the safety and quality of care provided to the public".

5. EASE OF USE: Easy ordering process, Fast delivery (Fast FedEx Delivery options, if available), Clear and Easy-to-undertstand Instructions for use.

6. DISCRETION: Discreet packaging - is it really necessary for your closest neighbor to know what was in that nice package you received yesterday :-).

7. PRIVACY AND CONFIDENTIALITY: Free consultation online: Like many people, you probably find the anonymity of an online medical consultation rather more pleasant than what could be an embarrassing conversation with your personal physician and his/her office staff.

You complete an online medical questionnaire which is thoroughly reviewed by a licensed physician, and if found suitable for treatment, the prescription will be dispensed and shipped by a licensed pharmacy.

If the consulting physician has any questions or concerns regarding your medical history or needs more information, he or she should contact you by email or by phone.

8. PRICE: Discounted, as much as possible, provided low prices does not mean low quality!

9. INTERNATIONAL ORDERS, if you do not live in the US. This should not be overlooked: Some online pharmacies only sell to customers in the US and Canada. And in some cases, they only tell you AFTER you've gone through almost the whole of the ordering process. This can be quite frustrating.

10. GOOD CUSTOMER SERVICE, including a toll free number for US residents and another number for international customers.

To be on the safe (and pleasant) side, always look for these top 10 qualities in an online pharmacy.

Online Pharmacy what you MUST Know

By : James Murray

At an online pharmacy, you can browse and shop for all the normal pharmacy items you are accustomed too, health care items, vitamins, over the counter medicines, weight loss products, diabetic supplies, and much more.

Also, at an online pharmacy, you have a choice to either visit the pharmacy (store) or have the online pharmacy fill and send your prescription through the mail. When you have your prescription drugs mailed, various pharmacies have to follow particular steps and special rules to check, fill and send your prescription drugs.

When you are at the online pharmacy website and filling out the forms with your name, address, etc. and your doctor's prescription information, they will also need a payment method to finalize the prescription order, plus any insurance payment information or medical plan you are using. Depending on which online pharmacy you use, they will either accept a payment online for delivery purposes or you will have to visit the actual store to complete the prescription payment process.

Also, one very important thing to consider at the online pharmacy your are using is that they have a secured checkout, payment system! An unsecured website will have a web address like http://www , where a secured website address will look like this https://www. The "s" at the end of "http" means it is a secured site. In future, any sites where you purchase items online make sure that this "https" configuration is in the website address, anything else can be hacked and your address, payment, and medical information stolen by Internet criminals.

Online pharmacy is the next generation of pharmacy, with the explosion of the worldwide web, every land based pharmacy will have a web presence, website, if they want to stay in business and be competitive in the pharmacy industry. When you finally select an online pharmacy website that you would like to do business with, check their site credentials, make sure that they are a "Verified Internet Pharmacy Practice WebSite" defined by the "National Association of Boards of Pharmacy." If you are concerned about the online pharmacy site and they aren't answering all your questions, there are many other sites on the Internet to choose.

One good tip about choosing online pharmacies is to select one that is associated with a large pharmacy chain, a well known pharmacy group. This way, you know the large pharmacy or someone else you know and has dealt when them before. The trust factor is minimized and your security, bank and credit information will be kept secured. "The Online Pharmacy" is the future of Pharmacy!

Just What Is Pharmaceutical Grade Fish Oil?

By : Dave Woynarowski, M.D.

The answer to that question would depend on who you ask.

If you asked the typical manufacturer of vitamin supplements, using standard food grade material, the answer would be “There is no such thing as pharmaceutical grade fish oil”. If you asked a practicing physician like me, I would tell you, “Pharmaceutical grade fish all is the only type of fish oil I would ever put into my body”. So just what does the term “pharmaceutical grade” mean?

First, it's important for you to understand that the FDA does not, at this moment, regulate vitamin supplements; therefore, any manufactured vitamin supplement is not evaluated by the FDA, so it’s not really a pharmaceutical.

Prescription drugs require very stringent purity and ingredient testing before they are considered safe by the regulatory bodies. In this country, technically speaking, food supplements do not require that high a degree of stringent purity testing.

However, a small band of manufacturers like me have dedicated ourselves to producing only the finest quality nutritional supplements. We therefore, use the term "pharmaceutical grade" to describe our products.

Simply put, what this means is, if the FDA were to make fish oil a prescription drug tomorrow, our product would pass muster. This is because we have stringent purity testing and allow no detectable levels of pollutants in our fish oil or any other of our products, for that matter.

This is a time-consuming and often expensive process, but yields the absolute best product money can buy. For the past couple of years, the debate has raged over pharmaceutical grade terminology. Many companies that do not apply the stringent high-grade procedures to guarantee the quality of their products are literally furious at the term “pharmaceutical grade”. They would like to see it banished from use because it puts them at a serious disadvantage. It earmarks their product, especially fish oil, as substandard.

Lets take a look at a recent Consumer Reports article on the purity of fish oil. Several different brands of fish oil were tested in this particular study. The conclusion reached was that all fish oils have about the same amount of pollutant levels, 1 ppm of lead, for example. Therefore the consumer should go out and buy the cheapest brand of fish oil possible since there would be no difference between them other than price.

Well my friend, the devil is in the details. Let's take our product Dr. Dave's Best Pharmaceutical Grade Fish Oil as an example. Recent independent laboratory testing yielded no mercury, and no lead at any detectable level. What this translates into is a purity of parts per trillion rather than parts per million. Those three zeros make a big difference. This could be the difference between you ingesting mercury at detectable levels in as little as one year’s time, versus ingesting no mercury over a lifetime.

Why is this important?

Mercury is the most toxic metal that naturally occurs on planet Earth. It would take only a very small amount of mercury in a water supply to make it undrinkable by the Environmental Protection Agency standards. Mercury can cause brain damage that looks very much like Alzheimer's dementia. You may have heard the term “mad as a hatter” from reading Alice in Wonderland, or simply as a cliché. Many years ago, hat makers used dyes that contained mercury, so they often suffered from severe brain damage as a result. As our population continues to age and brain health becomes a critical issue not just from Alzheimer's disease, but from other forms of dementia, it should become apparent that we should all strive to keeps our brains as healthy and toxin free as possible. This is one way in which my pharmaceutical grade fish oil stands out.

Now let’s take a look at lead. Most people know that lead exposure is toxic. In a particular area where I grew up there were battery plants. In these battery plants constant lead testing of the employees was undertaken to prevent permanent damage. Lead toxicity can have many serious consequences, including nerve problems, mental problems, blood problems, and kidney failure.

Sadly, lead and mercury are not the only pollutants found in our water supplies and our fish. Byproducts of the petroleum industry, including polyvinyl chlorides and biphenyl compounds are also found throughout the world. Some manufactures of fish oil note that all their fish sources come from above the Arctic Circle. This is the case with our fish oil also; however, we still subject it to very stringent purification methods using a proprietary process called molecular distillation. We do this because we recognize that even fish caught above the Arctic Circle are exposed to pollution. Therefore, where you catch your fish really doesn't matter all that much. What matters the most is what you do with your fish oil after you get it. Please do not be misled by anyone claiming that they have found a pure source of fish that requires no processing.

Some of the physical health problems associated with these types of petroleum pollutants include breathing problems, kidney failure, weakness and fatigue.

Taken as a whole, it is very important, that whatever you put into your body maintains the highest purity standards you can get, because you don't want to load up any of your organ systems, especially your brain and your heart with toxic pollutants.

There is yet another pollutant and a problem, which as far as I know, we are the only manufacturer who addresses. This is the problem of radiation.

Again, depending on where you catch your fish, you will see high levels of pollutants, among them radiation. For example, Pacific caught salmon have a higher underlying level of pollutants, including radiation.

You may have heard the term, Pacific Rim of Fire. The Pacific Rim of Fire stretches from the coast of California, up to Alaska, all the way down through Japan, and some of the islands of the Far East. This term basically refers to volcanic activity in the area where the bowels of the earth churn. They release extra radiation. Sadly, radiation pollution is a problem in this area of the world. No one is sure why there is extra metallic pollutants in Pacific salmon. It is simply a fact of life. At this time therefore, we use only Atlantic caught salmon, herring and other such oily fish from above the Arctic Circle.

It is amazing that some of this pollution can actually come from sunken Soviet nuclear submarines. This is in addition to background radiation. The chemical that is tested for in radiation testing is cesium. We maintain an extremely low level of background radiation in all of our products. Again, as far as I know, no one else even bothers to test for.

Is this stringent testing, that makes our product superior to all the rest on the market. Now let's look at some human examples. Let's say you wanted your mother or father to experience the benefits of my pharmaceutical grade fish oil. You could rest assured that you would not be in any way, causing harm to the fragile brain of an elderly person. Studies have shown that fish oil may indeed improve memory behavior and performance in the demented patient. Now let's look at the opposite end of the spectrum, a pregnant mother or newborn baby. There are many studies that show improved hand eye coordination and increased fetal development before birth. Fewer diseases of childhood and adult especially allergic diseases and in some cases, even a higher IQ in children who are adequately supplemented with omega-3 fatty acids from fish oil. For the teenager, there may be some serious benefits to acne, attention deficit disorder and concentration levels from taking fish oil as well. In each case, we cannot use the term treatment, because the FDA will not allow it, however in my own clinical practice, this is exactly the term I use. I do essentially use fish oil as a medicine. Therefore, I insist on only the highest quality for my products. Once again, if you were to take this and make it a prescription drug tomorrow, it would pass all the stringent testing the FDA would subject to. For this reason, we proudly use the term pharmaceutical grade fish oil.

There is another thing you should know about Pharmaceutical Grade Fish Oil. Because of its absolute purity, the most common side effect, "Fish Burp" is a rare occurrence indeed.

Dr. Dave's Best Pharmaceutical Grade Fish Oil, physician used, physician tested, my best to you and your family.

New Health Miracle -- Pharmaceutical Grade Fish Oil

Saturday, December 26, 2009

By : Bev Storer

“High-dose pharmaceutical-grade fish oil is as close to a medical miracle as we will see in the 21st century.” – Dr. Barry Sears

Dr. Barry Sears revolutionized nutritional thinking around the world with his 1995 landmark #1 New York Times best seller The Zone. With The Zone, and his subsequent bestselling Zone books, Dr. Sears describes how a scientifically proven plan of moderate carbohydrate consumption balanced with appropriate amounts of protein and fat may help you live a longer and better life.

In his latest best seller, The Omega Rx Zone, Dr. Sears greatly expands the potential of the Zone to alter how we think about optimal health in general. Drawing upon his own research, as well as recently published studies, he reveals how a revolutionary new technological advance in fish oil manufacturing, never before available to the general public, may be the magic bullet...

This new high-dose, pharmaceutical-grade fish oil is very rich in omega-3 fatty acids. Scientific evidence reveals a diet rich in long-chain Omega-3 fatty acids helps support:

* a healthy brain
* a healthy heart
* a healthy immune system
* healthy joint movement
* healthy kidneys
* balanced mood and sense of well being
* and, helps maintain cholesterol levels that are already within the normal range.

This new generation of fish oil is much different from the historical, impure, terrible-tasting cod-liver oil. As Dr. Sears points out, the fish oil doled out by our mothers and grandmothers, and currently sold at health food stores, has never been pure enough to be used in the quantities it takes to realize its potential benefits. The new pharmaceutical-grade fish oil is more concentrated, free of dangerous toxins, and has been clinically tested with spectacular results.

By following the Zone Diet and adding pharmaceutical grade fish oil to your daily routine, Dr. Sears believes that each of us will reach our maximum potential for optimal health.

Sanofi Pasteur has recalled four lots of its pediatric H1N1 vaccine in the US

Thursday, December 24, 2009

Sanofi Pasteur has recalled four lots of its pediatric H1N1 vaccine in the US that were found to have fallen below potency limits despite being be in spec at the time of manufacture.

The Centers for Disease Control and Prevention (CDC) said that the voluntary recall, which affects some 800,000 doses, is not related to any safety concerns and stressed that the vaccine is still expected to elicit a protective immune response.

The CDC also stressed that children who have already received the vaccine, which was shipped in November, do not need to receive a second shot apart from those aged under 10 in whom two doses of vaccine are recommended anyway.

To date, only Maryland and Virginia have confirmed they received vaccines from one of the affected lots, UTO23DA, UTo28DA, UTo2CB and UTo30CA, but neither could said how many doses had been used.

While the recall is obviously a concern for Pasteur and its French parent Sanofi Aventis, of perhaps more significance is its likely impact on public confidence in influenza vaccines, particularly those for H1N1 or “swine flu”.

Public concerns

Despite considerable public demand when the World Health Organisation (WHO) declared the H1N1 pandemic in June , anecdotal reports suggest that influenza vaccine uptake has been lower than expected.

Part of the problem is the perceived lack of severity of the circulating H1N1 virus which, while still responsible for significant numbers of deaths worldwide, has not hit the figures some predicted when the pandemic began.

There is also a vociferous anti-vaccination lobby, which has raised concerns that regulatory dispensations used to accelerate production mean that the available H1N1 vaccines have not been subjected to the same safety assessments.

This idea is reflected in a September survey by the Harvard School of Public Health’s opinion research program, which revealed that concerns about potential side effects was the leading reason (38 per cent) respondents said they would not the vaccination.

Unfortunately, this type of opinion is likely to be re-enforced by the Sanofi recall, which follows hot on the heels of a GSK request that Canadian authorities do not use 172,000 doses of its H1N1 vaccine .

Qualified Person (QP)

Qualified Person (QP) is a technical term used in European Union pharmaceutical regulation (Directive 2001/83/EC for Medicinal products for human use). The regulations specify that no batch of medicinal product can be released for sale or supply prior to certification by a QP that the batch is in accordance with the relevant requirements.(EudraLex, Volume 4, Chapter 1) The QP is typically a licensed pharmacist, biologist or chemist (or a person with another permitted academic qualification) who has several years experience working in pharmaceutical manufacturing operations, and has passed examinations attesting to his or her knowledge. The requirement for QP oversight has been extended to material for use in clinical trials since the introduction of EU Directive 2001/20/EC.

In countries that are part of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), the same role may be termed Responsible Person (RP) or Authorized Person (AP).

In Construction practice in the United States, a "qualified person" is someone who, by possession of a recognized degree, certificate, or professional standing, or who by extensive knowledge, training, and experience, has successfully demonstrated his ability to solve or resolve problems relating to the subject matter, the work, or the project.

wikipedia

Product Quality Reviews

A recent amendment to the EU Guidelines for Good Manufacturing Practice has introduced a requirement for holders of pharmaceutical Marketing Authorisations to carry out regular quality reviews on all of their products.

The incentive for this change came from a number of high-profile inspection failures and product recalls. Inspectors found that, over time, modifications had been made to manufacturing or testing procedures, specifications, equipment etc, which had not been incorporated into the regulatory approvals for the products.

The final version of the guideline was published in October 2005, and came into effect on 1 January this year. Medicines Inspectors will be looking for evidence that these reviews are being carried out and properly documented. Failure to do so will be highlighted as a deficiency in the inspection report, and could lead to action against the company and their Qualified Persons.

Companies that supply products to the USA will be used to providing Annual Product Reviews in the FDA format. The information required in the EU Product Quality Review is slightly different, so a separate document will be needed. The FDA review is intended to confirm that every batch of product released during the review period complied with the registered process and specification. The EU review concentrates on the quality systems and processes, to show that they continue to produce consistently good quality product. Inspectors will not expect to see reams of raw data, but the results of the analysis of these data and the implementation of appropriate process improvements.

The Product Quality Review can be used as part of a continuous improvement quality system to highlight where development resource can most effectively be targeted. It can:

• Decrease the risk of out-of-specification results
• Minimise the risk of rework/reprocessing
• Decrease downtime
• Increase productivity
• Decrease the risk of product recalls
• Meet all regulatory commitments/requirements
• Improve communication between production, engineering, quality and regulatory functions

The last point can be very important when activities such as production, distribution, stability testing or regulatory affairs are outsourced to other companies.

If the product is contract manufactured on behalf of the Marketing Authorisation holder, the Product Quality Review needs to be a joint activity between the MA holder and the manufacturer. In addition, the Qualified Person at the manufacturer must assess the final review document, to satisfy themselves that the process is in control, and that they can release batches for sale. This will require Technical Agreements detailing which company will be responsible for each aspect of the review, and the procedure for analysing data and producing the final document.

The review should cover the following:

Starting materials and packaging materials

Are they still being supplied by the source specified in the Marketing Authorisation? Has the specification changed, and is it appropriate to ensure the quality of the final product? Have the suppliers of active ingredients been audited to ensure that they comply with GMP? Have there been any problems with the suppliers, eg rejections of incoming batches?

Critical in-process controls and finished product results

Are these still the same as the ones in the Marketing Authorisation? Do the controls ensure that the finished product is of suitable quality? Are all test methods validated according to current standards?

Batch failures

How many batches were rejected during the review period? What investigations were carried out at the time? Were there any trends or similarities about the failures? Have any process changes been made to prevent recurrence?

Deviations and non-conformances

How many have occurred during the review period? What investigations were carried out, and what corrective and preventative actions were introduced to prevent recurrence? Were these actions effective? Was the Marketing Authorisation varied?

Changes to processes or analytical methods

Have these changes been properly authorised and validated? Has the Marketing Authorisation been varied to incorporate them? Have new or modified equipment or procedures been introduced that will require revalidation?

Marketing Authorisation variations submitted during the review period

This includes not only those that were granted, but also those refused, and those for third country (export only) dossiers. Does the Marketing Authorisation correctly reflect the manufacture and testing of the product? Why were variations refused; is more data needed?

Stability testing results

What are the results from routine stability testing of production batches? Do they still demonstrate that the product will meet the shelf-life given in the Marketing Authorisation? Are any adverse trends becoming apparent? (This may require additional statistical analysis of the results from all stability trials on the product). Are the tests and methods still appropriate for assessing the stability of the product? Do any changes to starting materials or processing methods mean that a full stability trial should be repeated?

Returns, complaints and recalls

How many of these have occurred during the review period? Were they adequately investigated, and what changes were implemented to prevent recurrence? Were these changes effective? Are there any trends to the complaints?

Adequacy of previous process or equipment corrective actions

Corrective and preventative action (CAPA) programmes will have been instituted to resolve problems arising during the review period, but did they fully achieve this? The Product Quality Review is a good time to confirm that CAPA programmes were appropriate, or to introduce further changes.

Post marketing commitments

Regulatory authorities often approve Marketing Authorisations provided that the MA holder commits to provide further information when available (eg samples of finished packs, ongoing stability data etc.). These are sometimes forgotten in the push to get a new product marketed and distributed. The Product Quality Review is a good time to confirm that these commitments have been fulfilled.

Qualification status of relevant equipment and utilities

Are utility systems such as HVAC, water or compressed gases still working appropriately? Have ongoing testing or monitoring results been reviewed for trends or failures? What investigations were carried out and were any corrective actions effective? Have any changes been made to these systems, and was requalification carried out?

Technical Agreements

Are there Technical Agreements with all suppliers and contractors, and are they up to date? Do they adequately reflect the activities and responsibilities of each party, and meet the requirements of the GMP guidelines?

Unlike the FDA Annual Product Review, there is no defined format for the completed report. The company is able to choose the format that is most appropriate for the product and the quality system.

Companies will need to establish where the information is currently held, and set up procedures and agreements to obtain it. While the final document must be assessed and signed off by the Qualified Person and the Marketing Authorisation holder, it would be acceptable to outsource the assembly and review of the raw data to an expert consultant.

Medicines Inspectors will be expecting to see the first Product Quality Review Reports, for a minimum review period of at least six months, during their inspections in 2006. Subsequent reports should cover the full twelve months review period.

It will require a significant resource to assemble, collate and review all of these data, but the cost savings from reduced batch failures and improved regulatory compliance should outweigh the cost of producing these reviews.

Robert Haslam
Somerset House Consultants