Thursday, October 1, 2009

Harmonized GMPs

There are movements to harmonize GMP regulations across countries and even across product types. The International Conference on Harmonization has been established to harmonize GMP regulations across countries. In addition, the FDA recently released a proposed rule for Current Good Manufacturing Practice Requirements for Combination Products (Federal Register, Docket No. FDA-2008-D-0409).

In this proposed rule, the FDA completed a gap analysis of the drug, biologic, and device GMPs. The purpose of this gap analysis was to determine what GMPs apply directly to combination products.

(i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity (single-entity combination products); or two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products (co-packaged combination products)).

The proposed rule lays out the missing drug requirements for device combination products and the missing device requirements for drug combination products.

Although the rule appears to be fairly well done, I was struck with its limitation to specific combination products.

So, I ask a question.

“Why shouldn’t manufacturers implement all applicable quality principles regardless of what regulations established them?”

I have spent the last three years working on a project that compiles European, United States, Canadian, and Japanese drugs, biologics, and device regulations into one harmonized auditing tool. Through this process, I have deduced that each set of regulations have merit in their own right, but none of them are comprehensive.

I have conducted many quality system evaluations as an industry auditor, FDA inspector, and GMP consultant. I have found that using a single set of regulations has significant limitation. In the process of harmonizing multiple regulations, I found it imperative to look beyond the letter of the text and appreciate the quality principles that were intended in their creation. In doing so, I discovered that some quality principles covered in one set of regulations were not adequately addressed in another set of regulations.

With the proliferated increase in the legal profession and law suits, a company’s regulatory compliance liability almost seems secondary. How many examples can we identified within the last decade where a company marketed an Agency approved product to only be sued for large sums of money after the fact. The cost of these law suits can be much greater than the cost of receiving a fine or warning from a Regulatory Agency.

I am sure that we can all appreciate that all quality issues have a potential legal liability and Regulatory Compliance is not likely to be a viable defense in the event of a lawsuit.

In today’s environment, I think it is safe to say;

“Simple compliance to any one set of regulations has limited quality value.”

Therefore, managing your company’s auditing and compliance program to successfully complete Regulatory Inspections may be short-sighted and is not likely to improve product quality or reduce a company’s legal liabilities. Conversely, applying the underlining quality principle found across multiple sets of regulations is likely to result in improved product quality, reduced legal vulnerabilities, and successful Regulatory Inspections.

Monday, September 21, 2009

Golden Opportunity to Reduce Regulatory Oversight of CMC Changes

In the summer of 2008, the FDA announced a pilot program for Biotech Manufacturers to submit Expanded Change Protocols (EC Protocol). This program mimicked an earlier pilot program established in 2005 for small molecule products.

The protocols are intended to gain additional product / process characterization data and pre-approved change evaluation methods in exchange for reduced regulatory filings. In other words, a change normally filed as a CBE-30 or PAS may qualify as an Annual Report (AR) filing, when executed according to an approved EC Protocol.

The FDA initially limited the number of original applications (INDs) to five, but they have recently extended the deadline for submission and has increased the number of allowable applications to eight (see the following link,

Although submitting the EC Protocol in an IND would be very advantageous for most manufacturers, it does come with a cost. It is likely to slow the progress and time to get a product to market. This being the case, only a few manufacturers can afford this luxury.

However, a single sentence in the last paragraph of the notice is rather intriguing; "FDA is also extending the deadline for submission of postapproval supplements from March 31, 2010, to March 31, 2011."

An EC Protocol submitted as postapproval supplement would not delay getting a product to market or restrict a product's marketability, while being refined through the approval process.

A savy manufacturer could submit a single EC protocol for all their facilities and products that could reduce the regulatory filing requirements for some of their most common and critical manufacturing changes.

Manufacturers don't need to request a blank check for all change supplements, but rather need to focus on getting reduced regulatory oversight on facility /equipment expansion and process improvement changes that allow them to improve their production outputs.

If interested in discussing the possibilities of reducing your regulatory oversight through a postapproval EC Protocl in more details, please contact me through my website,

Thursday, August 13, 2009

Meager Internal Auditing Program

This week, I will address the ninth of nine common CGMP Quality System shortcomings; Meager Internal Auditing Program.

Many of the internal auditing programs that I have witnessed are less than stellar. A collection of loose audit plans conducted by semi-qualified personnel is not a recipe for success.

Although auditing can be less than a glamorous job, a comprehensive auditing program is critical to implementing a successful Quality System. A robust auditing program can greatly increase the effectiveness of a Quality System by; ensuring raw materials are suitable for use, catching issues early enough to preventing them from becoming a crisis, facilitating methods for improvement, and eliminating the tragedy of significant regulatory deficiencies being discovered by the Authorities.

Many companies only expect auditors to have a minimal amount of experience and then rely on the auditor’s experience to do the job right. These companies treat auditing more as an art form instead of a regulatory science. This approach may work if the auditors are extremely experienced and had developed their own set of auditing tools, but the reality is that most experienced auditors are pursuing higher paying and more powerful positions.

To overcome this shortcoming, the Quality Units should establish a systematic audit program that relies less on auditor experience and more on robust auditing tools. Once established, retention of trained and qualified auditors should become a high priority. I have developed such a system that will transform a meager auditing program and train less seasoned auditors. See my website:

Thursday, July 30, 2009

Ineffective Training Programs

This week, I will address the eighth of nine common CGMP Quality System shortcomings; Ineffective Training Programs.

A routine part of any inspection or audit is to evaluate the training program.

Managing a training program is a monumental task. Consequently, I have found few training programs to be well managed and/or effective. Most training programs have a structure in place, but the effective implementation of that structure is often left to each Area Supervisor, who, in turn, may defer the training burden to their subordinates. This training program methodology very seldom works effectively.

In addition, training programs can become a check-in-the-box requirement. This becomes very evident, when re-training operators is a recurring corrective action for non-conformance investigations. I can appreciate the difficulty in effectively training the huge number of people need to perform the very complicated process of drug manufacturing, but a well managed and effective training program that minimizes human error is a critical element in any Quality System.

In reality, ill-trained operators can nullify some in-process controls.

To overcome this shortcoming, the Quality Units should routinely monitor the training program by correlating training effectiveness to encountered nonconformances and deviations.

Thursday, July 23, 2009

Resistance to New Technology

This week, I will address the seventh of nine common CGMP Quality System shortcomings; Resistance to New Technology.

New technologies can be a blessing or a curse. New technology has the potential to increase process controls and understanding, which can result in higher efficiencies, yields, and product. Conversely, new technology may also create havoc on established processes if implemented incorrectly or hastily.

New technology is also likely to require heavy regulatory scrutiny, which is a deterrent in of itself.

Therefore, the decision process for implementing new technology must weigh the benefit vs. the costs vs. the risk.

I am sure that we can all agree that every new gizmo should not be employed just because it exists. Likewise, it would be foolish to simply dismiss new technology because the burden of implementation and regulatory approval is significant.

To overcome this shortcoming, the Quality Units should explore the possibility of employing new promising technology, but should also considered all possible quality / regulatory ramifications and thoroughly test the technology before implementing it into commercial manufacturing.

Friday, July 17, 2009

Poor Quality Leadership from Senior Management.

This week, I will address the sixth of nine common CGMP Quality System shortcomings; Poor Quality Leadership from Senior Management.

I strongly believe that a strong quality environment is cultivated from the very highest levels of management. If senior management cares about quality implementation, then all levels of the company tend to buy into “quality matters”.

Inversely, if senior management doesn’t fully appreciate the direct connection between quality management and the bottom line, then a sub-robust quality system is likely to materialize.

A Quality Director isn’t likely to successfully implement a Robust Pharmaceutical Quality System, if Senior Management views the quality function as simple overhead. That Quality Director is likely to meet resistance at every turn and not receive the resources necessary to establish and maintain a health and effective quality system.

Unfortunately, it is unlikely the Quality Director will have the necessary influence to correct Senior Management’s quality short-sightedness, but it probably is worth an attempt. If all else fails, then it is probably best to search out a new corporate quality culture.

Thursday, July 9, 2009

Under Utilized Quality Tools

This week, I will address the fifth of nine common CGMP Quality System shortcomings; under utilized Quality Tools.

Modern Quality tools, such as SPC and PAT, can be very beneficial in establishing an effective Quality System. Ironically, many of the quality tools necessary to implement a Robust Pharmaceutical Quality System are already part of most Quality Systems. They just tend to be under utilized.

A significant under utilized tool is the Annual Product Review. I have found that most manufacturers complete this regulatory requirement simply to complete it, as opposed to completing it to gain product/process characterization knowledge. Most of the APRs I have read go something like this, “we produced “X” amount of batches, most batches meet specifications, root causes and corrective actions were completed for those that didn’t, and no negative trends were observed, therefore everything is beautiful and no process improvement is required. What a complete pencil whipping exercise.

Another under utilized tool is qualification/validation studies. These studies are often written to ensure that they pass. The functionality of these studies is to ensure all facilities, equipment, utilities, and/or processes are functioning sufficiently to ensure problems are minimized during commercial manufacturing. As a QA reviewer, I was often frustrated with change control requests that were submitted to fix problems with equipment or processes that recently passed validation activities. In these cases, validation activities were not completed appropriately.

To overcome this shortcoming, the Quality Unit should maximize the return from their established quality tools by complete more thorough and objective analyses and evaluations.