Friday, 27 February 2009

Validating Process Validation

By Agnes Shanley,

FDA’s new draft guidance gets to the essence of what process validation is, and isn’t. Have you read it yet?

Safe pharmaceutical manufacturing, as we know it today, could not exist without process validation. Introduced in the 1970s, when FDA was still known as the Bureau of Drugs, the concept was originally designed to protect the public against the impacts of variability in sterility assurance, but was extended broadly to drugs and devices.

It aimed to ensure that any process would do what its developers intended it to, and make products of reproducible quality. The concept worked.

It also became a monster. Over time, misunderstandings about validation promoted a rigid, bureaucratic approach to manufacturing. Concerns have led some companies to lock in inefficiencies, generate reams of defensive documentation, and reject new technologies or approaches, even if they would improve both process and product.

In addition to being far more engineering-focused and much more clearly written than the previous guidance, the new document stands out from the prior guidance in that it:

  • outlines, clearly, a life-cycle approach to process validation
  • presents the essence of what Quality by Design is, without going into the terminology
  • emphasizes the importance of process control, calling out the importance of both QA professional and the line operator in providing feedback and
    continued process verification.
  • specifically mentions process stability and process capability
  • mentions the potential role of simulation
  • touches on the importance of continuous operator training
  • highlights the need for a crossfunctional approach, even specifying the different disciplines that should, ideally, be involved.
  • discusses the need for data analysis, within and between product batches, mentioning the most relevant places to find this information:
  • discusses how PAT and real-time data access would change the approach to Performance Qualification

So what was so wrong with the prior guidance? I decided to check the wording of the 1987 document more carefully. It made me wonder about a few things….for one thing, where on earth did the magic number three (for the infamous “three validation batches”) come up? It wasn’t in that document.

The earlier document had already paved the way for QbD by highlighting the importance of drug development, yet it seemed to focus more on data collection than interpretation. It was also somewhat diffuse, taking many paragraphs to discuss control limits, and including lengthy asides on process examples that sounded like religious commentary on sacred scripts.

Some companies are already taking a very modern approach to process validation, and developing techniques that would allow processes to be adjusted on the fly. Last month, a meeting of the American Institute for Chemical Engineers (AIChE) in Philadelphia offered a number of practical examples showing how these concepts are being applied.

One expert from a U.K. company showed how multivariate models can be used to adjust automatically for differences in raw material sourced from different suppliers so that the resulting product’s quality is always consistent.

That is the future, but for many operations today it might as well be science fiction.
Recent informal surveys in our magazine have found that pharmaceutical development and manufacturing are still using mainly univariate rather than multivariate data, and that many companies aren’t even performing process capability analysis. The sigma level of drug manufacturing, experts say, remains around 3. At the same time, some FDA reviewers and inspectors may not be in synch with the new guidance. Audience members at one AIChE session asked why some FDA reviewers appear less interested in hearing about their carefully developed “design spaces” than in specific process values.

Even if there’s more work to be done, documents like this draft guidance provide clarity and a basis for open discussion and benchmarking. FDA is accepting comments on the document until January 19, via I urge you to write with any constructive criticism. In the meantime, write us and let us know what you think.

FDA publishes guidance on process validation

The US Food and Drug Administration (FDA) has issued draft guidance on process validation, updating its 1987 document to incorporate advances in manufacturing technology and thinking.

Modern risk management and quality system tools and concepts form part of the FDA’s new thinking, which is in keeping with its initiative entitled Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach”.

Biological products, including active pharmaceutical ingredients (APIs), are the focus of the document, which by implementing manufacturers should align their process validation activities with the product lifecycle concept and existing FDA guidance.

The document defines process validation: as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”

Covered under the guidance are some general considerations for process validation, such as having an integrated team that has members with a variety of specialisations, and more specific recommendations.

These recommendations span the three stages covered by process validation, namely process design, process qualification and continued process verification.

The three stages cover the adoption of process validation from development and scale-up through to commercial manufacture and beyond to provide ongoing assurance.

Included in the document are sections covering capturing process knowledge and understanding and facility design and equipment selection.

Documentation and analytical methodology are also covered in the guidance, which can be found here .

Asahi Kasei gains TechniKrom’s bioprocess business

Japanese chemicals firm Asahi Kasei has ramped up its bioprocessing operations with the acquisition of US industrial processing specialist TechniKrom’s biopharmaceuticals business.

The integrated offering, which will operate as a wholly-owned Asahi subsidiary, will combine TechniKrom’s portfolio of processing equipment and validation services with Asahi’s hollow-fibre and membrane adsorption technologies.

The deal, financial terms of which have not been released, builds on the firms’ collaboration centred on Asahi’s range of industrial Planova virus removal filters and, according to the Japanese company, will help drugmakers lower production cost and improve product quality.

Yasuyuki Yoshida, president of Asahi Kasei Medical, said the deal seems like a perfect fit in terms of the firm’s global expansion plan. He explained that the integration provides “a base for the development, production, and sale of equipment and systems in the US.”

While the US market for biologics and biotherapies has grown continually since it first emerged as a going concern 25 years ago, the development of follow-on biologics as patent expiry looms looks set to shift the expansion into a higher gear.

In recent months for example, several US majors like Pfizer and Merck & Co have expressed an interest in growing their generic biologics portfolio in preference to investing in the development of non-biologic drugs.

While such big pharma interest would have proved a barrier to entry for smaller firm’s wishing to claim a share of the traditional drug market, the greater technical difficulties associated with manufacture of biologics may mean there is more scope for technically proficient biotechnology companies to prosper alongside the industrial giants.

In addition, the Food and Drug Administration’s (FDA) recent approval of the first drug to be derived from transgenic-animals; GTC Biotherapeutics’ anti-clotting therapy Atryn, suggests that US demand for effective bioprocessing solutions will continue growing. All of which looks good for Asahi Kasei TechniKrom in terms of developing its business in the US.

TechniKrom President Lou Bellafiore was also pleased about the new relationship. He said that: “In addition to our existing products and services that we will continue to offer, we are extremely excited about the line-up of novel bioprocess separations products that Asahi Kasei TechniKrom will introduce."

Thursday, 26 February 2009

HVAC Excellence Test Validation Procedures

HVAC Excellence Test Validation Procedures

By John Hohman

Developing the content

Test content is developed through the input of technical experts. Traditionally called

“focus groups”, these groups have transitioned into groups now called “Subject Matter

Experts” or SME’s. To develop any national test, a minimum of five and a maximum of

nine technical experts from three states are essential. Ideally, the more participation from

more states is desired and sought.

A work session for the SME’s at the developmental stage generally consists of a “job and

task” analysis of the work done within the field of occupation that the SME’s represent.

A job and task analysis attempts to identify elements of the occupation that can be

identified as individual jobs. It continues to identify tasks that need to be completed

within each job element. There may be many jobs within an occupation and subsequently

many tasks that need to be done before a job can be completed. This is the first step in

developing “Content Validity.”

Depending on the scope of development, SME’s may be involved in identifying other

elements of the occupations, such as: tools, equipment, work environment, conditions of

work that relate to ADA (America requirements, etc. Sometimes this information is

already sufficiently documented and doesn’t require additional study.

Developing the structure

After the job and task analysis has been completed, the same or another group of SME’s

is retained to develop the structure of the test. The structure of a test is sometimes

referred to as the “table of test specifications” and is used to determine the content and

emphasis of the test. This is the part of the test building process that establishes

Construct Validity.”

It is generally understood that a group of questions (items) may constitute a test of

knowledge in a given field of occupation. Developing the table of test specification

maintains a degree of control on the content of the test. This process also satisfies the

condition of “Semantic Validity” whereby the labels relate to the occupation being

evaluated. This control of content helps to insure that one aspect of validity is maintained,

the second step for “Content Validity.”

The structure or table of test specification identifies the number of questions/items to be

applied to a given section/category of the test. Doing so maintains the content

relationship of the test while individual questions, relating to the section/category, may be

changed or randomly selected from a test item bank.

Developing the items

Questions on a test are typically referred to as “test items.” Each item takes the form of a

multiple-choice question. The item is made up of three parts: 1) the question, called the

“stem”, a single correct answer, and a set of plausible, possible answers called

“distracters.” The number of distracters sometimes helps to elevate the difficulty or level

HVAC Excellence Test Validation Procedures

By John Hohman

of the test. Typically there are four choices, one correct and three plausible distracters.

There can be up to seven choices for a given item.

The same or a similar occupational group of SME’s are involved with the development of

test items. Items are generated in many different ways, and they are guided by the “table

of test specifications.” More items are generated than the test requires. Often, items are

abandoned for many reasons and additional items are required to maintain the size or

length of a test.

Items are reviewed for “Bias” toward protected groups by persons other than the SME’s.

The test developer selects individuals that have a high degree of sensitivity to bias

language to review the developed test items in an attempt to eliminate all or most

language that may offend or bias an item for a protected group of people.

Pilot Testing

Pilot testing is an important step in the development of a test. Pilot testing consists of

identifying individuals within an occupation that are at approximately the target level of

the test. For example, a technician level test may require selecting individuals who have

some level of experience within the occupation to pilot the test.

Pilot participants are selected by knowledgeable people within the occupation. They are

asked to select participants who they feel are at the specific level the test is designed.

Through this selection process come aspect of “Criterion Related Validity” is generated.

Typically, selected participants have already been evaluated to some degree by the person

who selects them. Therefore, some degree of relationship exists between the level of the

participant and the level of the test. Other criterion related tests results might be used to

validate this process for a pilot group.

The size of the pilot test group will be selected to generate sufficient data. Depending on

the number of people within the occupation, the number within a location, or the number

of individuals that can be found to volunteer, will determine the pilot test group.

Face Validity” is generated at this point in the test development process. Face Validity

refers to the recognition of the test title, test categories, and test items as being part of the

field of occupation. Individuals who pilot test are asked to respond or comment on each

of these parts of the test.

The pilot test also asks participants to mark items, words or phrases that might have an

impact on protected groups in a second attempt to eliminate bias.

Item Analysis

Item analysis is the process of technically reviewing the structure, response, and fit of a

given item and the relationship of that item to the rest of the test. Through item analysis

HVAC Excellence Test Validation Procedures

By John Hohman

some levels of “Reliability” validation can be obtained. Item analysis can use any or all

of the following statistical analysis:

Kuder Richardson Formula - KR 20 & KR 21

Cronbach Coefficient Alpha

Spilt-half Reliability Coefficient

Level of Difficulty

Easiness Scale

Coefficient of equivalence


Standard error of measurement

Final Formatting

The item analysis will reveal items that are not working as expected. Those items will

either be eliminated or the deficiency repaired. The test will be formatted to the correct

number of total questions and each section/category is reviewed for the correct number of

questions according to the table of test specifications. All other spelling and formatting

difficulties are eliminated.

Test Delivery

Delivery of the test follows prescripts required for all national tests and requires a level of

security. The delivery process consists of identifying individuals to proctor the test who

have a high degree of personal conviction and agree to the requirements of handling and

proctoring a national test.

Continuing Analysis

Test results are continually monitored on a periodic basis. As score anomalies occur,

whole tests or individual items are scrutinized for problems. When a test shows a

significant level of problems it is slated for review ahead of its scheduled review period.

All tests are reviewed on a three year basis.

Thursday, 12 February 2009

Natural Health Cures - Don't Check Your Brain at the Door

While researching an article for my site, I visited several popular forums featuring home health cures. I was surprised at the level of distrust and skepticism directed toward our health care system in general and pharmaceutical companies in particular. Although not a strong supporter of either, what struck me the most was the lack of thoughtful consistency when it came to natural health cures and remedies.

It was almost as if the assumption was that if it was natural, homeopathic or an old world type of remedy, it was somehow better, safer and more effective than anything a medical doctor could offer.

While many of these could people have a healthy skepticism when considering pharmaceutical company intentions and ability to help control and illness, they blindly follow the natural health cure mantra.

Home remedies are also preferred by many because of a belief that the pharmaceutical companies are not interested in your health. While there are many examples of big drug companies greed and avarice, their products are very widely used and are considered both safe and effective. Make no mistake, this does not mean that they can be used without risk or should be used by just anyone.

While many of our most effective medications used today originally came from plants, this should not be used as a basis to assume that any plant is safe. Buttercups, Oleander and even a common house plant known as creeping Charlie are all considered poisonous. Here's a link to the Cornell University poisonous plant listing for more information.

The point is that as consumers, we should not assume that everything with a natural label should be considered safe or effective. We should have the same healthy skepticism when considering natural cures and remedies that we show toward big drug companies.

We also need to consider the usefulness of testimonials. While a testimonial may offer some validation or a product, it should not be a major consideration for your purchase or use. The difference between a testimonial and the research done by the drug companies is like night and day.

Research is done to demonstrate the usefulness of a compound in a variety of people and situations, measuring the effectiveness and appropriateness of the product. A testimonial is based on one persons experience with a product. No information is usually offered about how the product was used, dosage or side effects experienced. Further, a testimonial also is based on the perspective on the person offering their opinion.

While many natural remedies and cures do indeed work, don't allow your preference for these products to over ride your good common sense.

Pharmaceuticals Contract Manufacturing

Pharmaceuticals contract manufacturing offers support for the design and manufacture of pharmaceuticals. Contract manufacturers usually produce high quality and highly secure pharmaceuticals at low prices. Most of the contract manufacturers help their customers in the production, finance, marketing, distribution and program management of pharmaceuticals. Many pharmaceutical companies seek the help of contract manufacturers to produce a product economically, within a time period. Contract manufacturers often work together with these companies to create the best possible products.

The major pharmaceuticals contract manufacturing capabilities include solid dose tablets, capsules and oral liquid production. Other pharmaceuticals contract manufacturing services are process development, clinical supplies manufacturing, analytical method development and validation, stability testing programs, technical transfer, process scale up and validation, regulatory consultation and unit dose blister packaging with bar coding. Many pharmaceuticals contract manufacturers deal with the manufacturing and development of sterile liquids and lyophilized products in solid, semisolid and liquid dosage forms. A few contract manufacturers also provide assistance with formulation and development, production scale-up, regulatory consultation, secondary manufacturing and primary and secondary packaging.

Pharmaceuticals contract manufacturers reduce the cost and time of production. Thus they provide a service extending capacity for pharmaceutical and biotechnology companies. Pharmaceuticals contract manufacturing is the high quality and economical alternative to small and medium sized biotech and diagnostic companies. Contract manufacturers usually serve as partners for the smaller and virtual organizations to provide services that require too much time and large financial resources. The larger pharmaceutical companies can also reduce their cost of production by outsourcing to contract manufacturers having more experience and resources.

Contract manufacturing requires clear deliverables to keep the project focused and to manage it easily. Pharmaceutical contract manufacturers need to immediately communicate with their clients when technical issues occur. The original companies should act as extensions of the pharmaceutical company. Since the main feature of pharmaceutical contract manufacturing is the quality of products, contract manufacturers must know all the needs of the customer. It is better to execute a quality agreement between the company?s responsibilities and expectations.

A Standard Procedure For Quality Assurance Deviation Management

What is a Deviation:
A Deviation is a departure from standard procedures or specifications resulting in non-conforming material and/or processes or where there have been unusual or unexplained events which have the potential to impact on product quality, system integrity or personal safety. For compliance to GMP and the sake of continuous improvement, these deviations are recorded in the form of Deviation Report (DR).

Types of Deviations:
1. Following are some examples of deviations raised from different functional areas of business:
2. Production Deviation - usually raised during the manufacture of a batch production.
3. EHS Deviation - raised due to an environmental, health and safety hazards.
4. Quality Improvement Deviation - may be raised if a potential weakness has been identified and the implementation will require project approval.
5. Audit Deviation - raised to flag non-conformance identified during internal, external, supplier or corporate audits.
6. Customer Service Deviation - raised to track implementation measures related to customer complaints.
7. Technical Deviation - can be raised for validation discrepancies. For example: changes in Manufacturing Instruction.
8. Material Complaint - raised to document any issues with regards to non-conforming, superseded or obsolete raw materials/components, packaging or imported finished goods.
9. System Routing Deviation - raised to track changes made to Bill of materials as a result of an Artwork change.

When to Report Deviation:
A Deviation should be raised when there is a deviation from methods or controls specified in manufacturing documents, material control documents, standard operating procedure for products and confirmed out of specification results and from the occurrence of an event and observation suggesting the existence of a real or potential quality related problems.

A deviation should be reported if a trend is noticed that requires further investigation.
All batch production deviations (planned or unintended) covering all manufacturing facilities, equipments, operations, distribution, procedures, systems and record keeping must be reported and investigated for corrective and preventative action.

Reporting deviation is required regardless of final batch disposition. If a batch is rejected a deviation reporting is still required.

Different Levels of Deviation Risks:
For the ease of assessing risk any deviation can be classified into one of the three levels 1, 2 & 3 based on the magnitude and seriousness of a deviation.

Level 1: Critical Deviation
Deviation from Company Standards and/or current regulatory expectations that provide immediate and significant risk to product quality, patient safety or data integrity or a combination/repetition of major deficiencies that indicate a critical failure of systems

Level 2: Serious Deviation
Deviation from Company Standards and/or current regulatory expectations that provide a potentially significant risk to product quality, patient safety or data integrity or could potentially result in significant observations from a regulatory agency or a combination/repetition of "other" deficiencies that indicate a failure of system(s).

Level 3: Standard Deviation
Observations of a less serious or isolated nature that are not deemed Critical or Major, but require correction or suggestions given on how to improve systems or procedures that may be compliant but would benefit from improvement (e.g. incorrect data entry).

How to Manage Reported Deviation:
The department Manager or delegate should initiate the deviation report by using a standard deviation form as soon as a deviation is found. Write a short description of the fact with a title in the table on the form and notify the Quality Assurance department within one business day to identify the investigation.

QA has to evaluate the deviation and assess the potential impact to the product quality, validation and regulatory requirement. All completed deviation investigations are to be approved by QA Manager or delegate. QA Manger has to justify wither the deviation is a Critical, Serious or Standard in nature. For a deviation of either critical or serious nature QA delegate has to arrange a Cross Functional Investigation.

For a standard type deviation a Cross functional Investigation (CFI) is not necessary. Immediate corrective actions have to be completed before the final disposition of a batch. Final batch disposition is the responsibility of Quality Assurance Department.

If a critical or serious deviation leads to a CFI, corrective and preventive actions should be determined and follow up tasks should be assigned to area representatives. Follow up tasks should be completed within 30 business days of the observation of deviation. If a deviation with CFI can not be completed within 30 business days, an interim report should be generated detailing the reason for the delay and the progress so far.

After successful completion of the Follow up tasks Deviation should be completed and attached with the Batch Report /Audit report/ Product complaint report /Safety investigation report as appropriate.

What To Check During The Deviation Assessment:
QA delegate has to conduct a primary Investigation on the deviation reported and evaluate the following information

1. Scope of the deviation - batch affected (both in-process and previously released)
2. Trends relating to (but limited to) similar products, materials, equipment and testing processes, product complaints, previous deviations, annual product reviews, and /or returned goods etc where appropriate.
3. A review of similar causes.
4. Potential quality impact.
5. Regulatory commitment impact.
6. Other batches potentially affected.
7. Market actions (i.e. recall etc)

Essential elements of a good quality management system are described in this article for pharmaceutical industry. Check more in Pharmaceutical Quality Procedures

Auditing Process Validation


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

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

Challenge of the Auditor’s Role

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

• Prior internal audit commitments

• Customer audit commitments

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

• FDA commitments (filing or inspection)

When are Process Validations (or Revalidations) Required?

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

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

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

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

Validation Types

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


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


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


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

Process Validations (Process Qualifications)

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics. The intent is to demonstrate that a process repeatedly yields product of acceptable quality. A minimum of 3 consecutively successful cycles—on a given piece of equipment using a specific process—constitutes process and equipment validation. Not only is the process under scrutiny, but the piece of equipment used to deliver that process is as well. Process operating limits should be tested, but not edge of failure. “Robustness” and “worst case” are common goals.

Activities that Occur in Advance of Process Validation

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

Upstream Tasks to Minimize Variability

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

–Employee training

–Equipment IQ, OQ, Calibration & Maintenance

–Component specifications

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

–Qualification of key production materials

Importance of the Protocol

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

Protocol & Acceptance Criteria

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

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

FDA’s Perception of the Role of the Quality Unit

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

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

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

Failure to Meet Acceptance Criteria

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

Validating a Transferred Process

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

Validation of Transferred Technology

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

Questions Often Asked During Technology Transfer

Raw Materials

Do specifications exist?

Do they make sense?

Are the test methods reliable?

Are the specifications needed?

What should be specified but isn’t?

What is the source of raw materials?

Are there more sources?

What is the grade to be used?

Are the grades interchangeable?


Does the plant have the proper equipment?

Are the batch size and equipment matched?

Does an alternate supplier exist?

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

Process Parameters

Are the set points too narrow?

Are the set points too wide?

How were the set points determined?


How do I sample?

What do I sample?

Where do I sample?

Why should I sample?

How much sample should I take?

What does the data mean after it is obtained?

Final Product

How were the specifications set?

Are the tests reliable?

Janet Neeley has more than 20 years of experience in the biologics, device/diagnostics and pharmaceuticals fields with recognized expertise in the management of CGMP operations. She has been directly responsible for overseeing the manufacture of cancer therapeutics and imaging agents, including the validation of systems, equipment, and processes for cleanroom operation. Experienced in contract pharmaceutical goods/services oversight, Neeley has developed numerous procedures and quality agreement formats to ensure the adherence to FDA regulations by domestic and international contractors.

Web Document Management For the Pharmaceutical Industry - 7 Features and Benefits Worth Paying For

With the FDA's Critical Path Initiative paving a new road for various industries in the life sciences sector and the 21 CFR Part 11 regulation implicitly recommending the automation of quality and compliance process management in pharmaceutical environments, change is on the horizon for the burgeoning pharmaceutical sector.

Automation in the Pharmaceutical Sector

If your company, like other pharmaceutical companies, is considering the automation of GxP process, quality management, quality audit, compliance and document control processes, consider the following benefits that increased automation in the pharmaceutical sector should provide:

  1. An increased ability for participants to virtually communicate regarding process information, documentation, etc.;
  2. Full or partial elimination of redundant and iterate administrative tasks often associated with excessive man hours and spare amounts of actual production or achievement (i.e. using manual process to manage documentation essential to the approval and future of billion dollar drug compounds);
  3. A more effective unification of quality departments with all other area departments (purchasing, manufacturing, etc.) in terms of understanding and real-time information. In other words, pharmaceutical professionals need to know how the processes they adhere to affect other processes throughout the company.

Achieving Automation Goals

To achieve automation goals, most pharmaceutical companies would do well to start by investing in a web document management solution that can be launched from the same platform as other solutions designed for the life science industries (i.e. GxP process control, quality management and quality audit solutions). The web document management software should also provide the following features and benefits:

#1: A History of Successful Validation

Quality assurance professionals and other pharmaceutical professionals know the importance of reputable software validation. When searching for a web document management solution, pharmaceutical professionals should pay close attention to its validation history.

#2: Speed

Let's get real. The only reason any pharmaceutical company would even consider the purchase of a web document management solution would be to save money and time on the product-to-market pathway. If any given solution does not automate and increase the speed of document change processes, document approvals, notifications and document distribution, then the solution isn't worth consideration.

#3: Time Required for Installation, Implementation and Validation-Affects on ROI

Some software vendors may tout the strengths of their software and its immediate capacity for providing a healthy ROI. However, they may conveniently fail to mention that their installation, implementation and validation processes may stretch into 6 months, a year or even longer. Pharmaceutical professionals need to search for a web document management solution that provides a healthy ROI but that makes a clear statement regarding the time that will be required for installation, implementation and validation. A clear statement will allow pharmaceutical companies to make transparent decisions and effective planning for the upcoming transitions that are inevitably linked with the switch to automated document control.

#4: Configurable and "Off-the-Shelf"

If pharmaceutical companies prefer an off-the-shelf web document management solution, it must still be configurable to the unique needs of every company that purchases it. Some pharmaceutical companies for instance may not apply the same steps throughout a routing or collaboration process and the web document management solution should be able to reflect that.

#5: Tracking and Audit Trails

The web document management solution should also provide tracking and audit-trail features as well as sophisticated revision controls and reporting features.

#6: Electronic Signature Controls

To comply with 21 CFR Part 11, pharmaceutical companies must employ electronic signature controls. A web document management software solution that automates document signings routing and collaboration is highly recommended.

#7: Compatibility with Other Existing Solutions

As mentioned earlier the web document management solution should be launched from a platform that will allow for the future launch of other solutions. These solutions may include GxP process solutions such as software for deviations identification, nonconformance identification, quality audit, customer complaint handling, change control and CAPA solutions. A submissions management solution particular to the pharmaceutical industry is also highly recommended.


Pharmaceutical companies are in a period of great opportunity and should be implementing less administrative man power and more time into research and development. The right software solutions can allow pharmaceutical companies a greater opportunity to do so.

Marci Crane is a copywriter for MasterControl in Salt Lake City. For more information in regard to web document management solutions, please feel free to contact a MasterControl representative