GMP and Product Development Phases

HeaderGoodThousands of biotech pharma companies are conducting excellent research for the development of novel medicines for existing and unmet needs. According to clinicaltrails.gov, there are at this time more than 115,000 clinical trials being conducted in the US alone with around 22,000 studies in pre or clinical phase 1, 29,000 in clinical phase 2 and 13,000 in clinical phase 3 representing different stages of product development. While the major focus of the pharma developing early clinical trials materials is on the R&D, it is important to note that GMP knowledge and implementation is equally important.

How much GMP?

The plain and simple answer could be “never enough”. However, unless the company has a constant flow of revenues, never enough may not be the right approach. In this article, I will discuss the minimum GMP requirements for early phase companies, at different stages of development.dreamstime_xs_133354704

The question, a clinical phase company should ask is when was the last time, some expert quality personnel audited the process from receipt of raw material like a cell line to clinical trials material release and subsequently to clinical outcomes if any. If the answer is “never” or “a long time ago” then the company may be in for surprises in the data generated. Another important point to remember is that R&D should never be controlled yet must be challenged from time to time through development life cycle documents and quality personnel.

The failure rate of clinical trial materials and outcomes is sometime alarmingly high, which leads to failure of the company to progress. Could the excessive failure rate be because of this lack of challenge to the process in general and R&D in particular? The answer could very well be YES. GMP is a state of mind which in a strange way closely resembles R&D with the queries of how and why.

The common perception of no GMP for phase 1 and pre-clinical studies is totally misleading, partly confused by 21 CFR 210 final rule which states that 21 CFR Part 211 does not apply to investigational drugs for use in phase 1 clinical trials.  The reason for this confusion is that we tend to miss the requirements that follow it up as “unless the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study” and the requirement of GMP for this phase in the form of different FDA and other guidance. In short, GMP is needed at all stages where a product is intended for human use regardless of its development phase. The difference of the state of GMP in different phases of development is the degree of GMP in terms of the knowledge acquired as the product moves from pre-clinical to phase 1 to phase 2 to phase 3 and commercial.

Critical GMP Parameters

Here are some critical GMP parameters with respect to different phases of development:

GMP

  1. Calibrated equipment shall be used and a strong equipment maintenance program shall be in place starting with the R&D and be finalized before the start of the phase 1 development.
  2. The proposed design of the facilities, utilities and equipment used shall be suitable for intended purpose. Design Review / Qualification shall be initiated before systems / equipment are shipped to the site.
  3. Analytical methods shall be qualified at the pre-clinical (Tox) phase with qualification completed by phase 1. A method can only be considered qualified if the system it is executed on is qualified first. The degree of system qualification in turn need associated impact and risk assessment of the system, its functions and components for its impact on the quality of the product in the given development phase. Therefore, it is recommended that system impact assessment, function criticality assessment, and component criticality assessment be initiated as soon as possible, preferably in the pre-clinical phase.
  4. Analytical method validation shall proceed from phase 1 and continue into phase 3 as more information is accumulated during product development.
  5. Systems / Equipment shall be qualified for phase 1 development use, with the risk and criticality assessments completed at the beginning of this phase.
  6. Bioburden and Endotoxin Controls shall be in place at the beginning of phase 1 development and continue into BLA submission phase (phase 2b or 3) as more information is collected about the product.
  7. Process validation shall begin at the latest at the start of BLA submission phase and completed before the end of this phase.

Final Thoughts:

While the GMP rules are considered as designed to ensure patient safety, let us not miss out on the opportunity that these rules give us in ensuring smooth sailing from development to approval. The era of keeping clinical trial outcomes separate from development, manufacturing, and quality control departments is over as Biotech products are extremely sensitive to minor CMC changes. The separate phases of clinical trials and development are fading as we enter the world of biotech products where cohort studies are used for BLA submissions in phase 2.

Written By: Abdul Zahir, Project Manager III

ICQ

 

References:

PDA Technical Report 56

EudraLex Volume 4

21 CFR Parts 210, 211, 600

International Committee on Harmonization (ICH) Q8, Q9, Q10

Analytical Procedures and Methods Validation for Drugs and Biologics: July 2015

FDA Quality Issues for Clinical Trial Materials: The Chemistry, Manufacturing and Controls (CMC) Review

ASTM International – Designation E2500-07

Statistical Process Control, Friend or Foe?

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In my experience, I see a lot of companies using trend charts and statistics to get a view of their process, when what they are actually doing is avoiding looking at their processes and waving meaningless numbers around.  While this doesn’t seem to make sense, when I look at the misuse of the data, I see many of the same issues across many different sites.

It seems a lot of companies get asked to look at metrics or trend their performance. While the trending of discreet process outputs, yield etc. is easy and straightforward, they sometimes get bogged down in reviewing more in-depth process performance.  This would include things like the health of a quality system, or of something like a manufacturing process.

Same Old, Same Old…The Same Old Thinking The Same Old Results

In general, I see a lot of companies take this typical approach.

  • Get asked to trend a process
  • See what data is readily available
  • Put that data in a trend chart
  • Review that data regularly
  • Initiate no formal projects, or take any meaningful action when the process isn’t trending well
    1. Typical responses are to tell people to work better to fix the metrics
    2. Change the metric they are looking at
    3. Ignore it and hope it goes away – primarily because they haven’t really accepted that this is a true measure of the process success

Taking a Different Vantage Point

Conceptual hand writing showing Think Outside The. Business photo text Creative Thinking Looking in different perspective

It’s interesting that the idea of statistical process control can be traced back to some of the Deming principles and the system perspective, however most people don’t even consider a system perspective when developing statistics.  Let’s look at the system perspective and the best way to develop statistics and how to use them for improvements.

In the system perspective we recognize that all outputs are part of a system, and not independent results.  In the system perspective we can view a system as a long pipe.  At the end of the pipe is the expected output (what we think of as success).  At the beginning of the pipe are the inputs to the system.  The pipe is the system that transforms the inputs to the outputs.  We want to determine how to measure the system success we need to evaluate what successful outputs are to that system.

This is a staged process.

  • What are the outputs of the process?
  • Who are the customers (stakeholders) for those outputs?
  • What are the needs of those customers?
  • How can we measure those needs?

By walking through these questions, you can develop the key metrics to determine the success of the system. You may have to take new measurement or generate data that isn’t already available, but it can also lead us to the best way to make improvements to the process.  Too often we just rely on the easy data that we already have available without even thinking what this tells us about our process.

Set up for Success

We need to follow the steps below which are above and beyond what is typically done;

  • Determine the system you want to look at
  • Go through the previous 4 step process to determine key metrics
  • Measure the system metrics
  • When something statistically does not meet out criteria, evaluate what in the system we can do to improve the output (initiate a project team as needed to evaluate process improvement)Strategy Execution Success concept words
    1. Process improvements should look at all inputs to a system (Man, Machine, Methods, Environment, and Materials)
  • Make Improvements
  • Measure success of the updated system
  • Continue to monitor

This is a very high-level view on how to truly measure and improve our systems.

Final Thoughts

We as an industry need to get past the idea of just asking our people to be the sole way to improve outputs when there may be something else broken in the system. We need to be sure we are looking at true measures of success, so that we really do feel motivated to make improvements when we don’t meet expectation.

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Written By: Michael Murphy, Managing Consultant

ICQ Consultants is Hiring!

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ICQ will be attending the 2018 ISPE Biopharmaceutical Manufacturing Conference in CA

biopharma18-event-page-thumbnail-360x170The 2018 ISPE Biopharmaceutical Manufacturing Conference focuses on the quickly evolving science of biologics manufacturing for new modalities. From leveraging existing capacity with novel processes, to implementing new and emerging technologies, this conference will bring together experts and leaders to ensure the Biomanufacturing industry successfully prepares to manufacture these novel medicines to deliver on our promise of supplying life changing medicines to patients across the globe. ICQ’s Michael Bogan and Michael Gatta will be in attendance.  Don’t forget to register to attend!


Please stop in and meet the team from ICQ at Booth 307 at this years 2018 ISPE Biopharmaceutical Manufacturing Conference held from December 10th through the 12th at the Hyatt Regency Huntington Beach in Huntington Beach, CA.


ICQ Consultants continues to grow….

ICQ Consultants continues to expand, hiring for several new positions in Greater  Boston, Greater Baltimore, and Greater San Francisco Areas. If  you NowHiringare considering a career change, we would love to hear from you.  Visit our Career page today!


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Getting Smart with Utilities Sampling

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In the pharmaceutical industry utilities sampling is done for a number of reasons such as regulatory requirements, quality control, process control, investigational purposes, diagnostic purposes, or Test Method Validation to name a few.  Therefore it is important to understand what a sample is and why they are important.

Simply put, the purpose of sampling is to collect a small representative fraction of a much larger lot that accurately represents the composition of the lot.  The sampling process should not modify or change the collected sample in any way.  However in many cases this is a practically impossible proposition as all sampled utilities come into contact with air and containers during the sampling process.  Sample handling concerns can be reduced and sometimes eliminated altogether by monitoring quality parameters usingdreamstime_xs_59774316 in-line, on-line, or at-line monitors. Quality attributes most commonly monitored are microbiological and endotoxin varieties, Total Organic Carbon (TOC) and conductivity. Unfortunately, many times a quality attribute of interest cannot be analyzed by such an instrument as previously described.  In these cases a sample must be taken from the utility stream and evaluated off-line.

Sampling effectively is of the highest importance to the success of any pharmaceutical critical utility system. However, when it comes to sampling there is not much regulatory guidance. So collecting a representative sample from a utility system can be a difficult and complex process. Inaccuracies may be introduced in any number of ways such as:

  • environmental conditions
  • sample valve design
  • sample point location
  • procedure, container type
  • sample handling, sample storage and transport

The effect of these aspects is common and occurs throughout industry.  As a result, errors due to sampling happen frequently.  To mitigate sampling errors establish good practices by improving upon:

  • How you determine sampling locations
  • Developing sampling plans
  • Sample valve designs
  • Sampling Techniques
  • Handling Samples
  • Training for personnel performing the sampling

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During a particular startup, renovations in the supporting QC laboratory areas were also ongoing.  Unbeknownst to the startup team, sterility samples were stored and manipulated in a non-controlled space adjacent to the laboratory due to space constraints.  When sample failures were noticed, an investigation of all the above listed criteria were performed. Finally, the space and lack of controls were identified and found to be the root cause of the failures.  Communication of all “non-ordinary” aspects of a project is essential to minimize risk and work towards the successful and timely completion of sampling.

Improper sampling can be responsible for creating Out Of Specification (OOS) data and prompting investigations into a system that is actually providing suitable quality. Or conversely, improper sampling could create a more dangerous situation where the quality is in fact OOS, but the data falsely indicates that the quality is acceptable. In either instance, there could be adverse effect on company image, budget, production, integrity, and regulatory accountability, all brought about from improper sampling.

So get smart about your utility sampling!

 

Reference: ISPE Good Practice Guide: Sampling Pharma Water, Steam, & Process Gases

 

Written By: Nathan Roberge, Consultant IIIicq-22.jpg


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ICQ will be attending the 2018 ISPE Annual Meeting & Expo in PA

Image result for ispe 2018 annual meetingThe 2018 ISPE Annual Meeting & Expo is a four day event for professionals at all levels of the industry from young professionals to the most senior executives, Communities of Practice, special interest groups, pharmaceutical industry equipment and services, suppliers, and regulatory professionals.  The expo will feature an extensive expo hall with more than 300 companies in attendance.  There will be two days of training plus an array of workshops offered.  Don’t forget to register to attend!


Please stop in and meet the team from ICQ at booth 1106 at this years 2018 ISPE Annual Meeting & Expo held from November 4th through the 7th at the Pennsylvania Convention Center in Philadelphia, PA.


ICQ Consultants continues to grow….

ICQ Consultants continues to expand, hiring for several new positions in Greater  Boston, Greater Baltimore, and Greater San Francisco Areas. If  you NowHiringare considering a career change, we would love to hear from you.  Visit our Career page today!


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ICQ will be attending the American Pharma Outsourcing Summit 2018 at the Crown Plaza Hotel, Cherry Hill, NJ

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The American Pharmaceutical Outsourcing Summit is designed to provide pharma outsourcing executives with current trends, strategic insights and best practices in manufacturing, outsourcing, capacity management, quality assurance, quality control, regulatory compliance, operation excellence, supply chain, and logistics. Network with over 150 of your peers as we explore strategies to maximize efficiency while remaining compliant in an ever-evolving environment.


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Michael Gatta, Principal of ICQ Consultants will be hosting a round table discussion: “Challenges to Maintain Consistency of Validation Practices from the Operating Company  to the CMO.”

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Please stop in and meet the team from ICQ at booth 16 at this years American Pharma Outsourcing Summit held on October 2nd and 3rd at the Crowne Plaza Hotel in Cherry Hill, NJ.


 

ICQ Consultants continues to grow….

ICQ Consultants continues to expand, hiring for several new positions in Greater  Boston, Greater Baltimore, and Greater San Francisco Areas. If  you NowHiringare considering a career change, we would love to hear from you. Visit our Career page today!


Join our network, follow us and share this on LinkedIn, Google +, Twitter and Facebook so you can see other new and exciting news and discussions being posted by ICQ Consultants.

Thank you for visiting!

ISPE BannerThank you to everyone for stopping by and visiting with ICQ at the 2018 ISPE Product Show, it was great to see new faces and re-connect with old friends.  Congratulations to the winners of our giveaways, we look forward to connecting with you all again!ISPE Booth

 

ICQ Total Benefit Compensation Package – Better Insurance and More time Off!

ICQ Total Benefit Compensation Package

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Did you know the average monthly premium for a family plan for health insurance nationwide is $833.00 per month? Since the passage of the Affordable Care Act, Americans who make a certain level of income and are without health insurance have been financially penalized. ICQ provides premium free health insurance to all of its full time W2 employees. The total compensation package for someone making $104,000.00 per year or $50.00 per hour is equivalent to making $133, 244.92 per year or $64.06 per hour.


ICQ Bench-marked Benefits Against Competitors

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Identifying System Boundaries in a few easy steps: so easy a cave man can do it!

Identifying System Boundaries in a few easy steps: so easy a cave man can do it!

CavemanSystem boundaries are the foundation of the Engineering lifecycle.  These boundaries identify where one system ends and another begins.  System boundaries define the scope of a system and assist in the management of Validation, Maintenance and Change Management processes.  Without these boundaries defined, the chances of omitting components or lines during validation or maintenance increases which can increase your chances for a regulatory finding. Identifying boundaries on the Process and Instrumentation Diagrams (P&IDs) is ideal to ensure that they are also aligned with maintenance activities, but at a minimum these boundaries should be clearly called out within the scope of the commissioning and qualification protocols.

The task of identifying system boundaries seems like it should be easy to accomplish, however there are several things to consider ensuring that boundaries are defined consistently to all systems.

  • Does this system supply multiple systems (water, steam, …)?
  • Is your system a packaged system or skid (autoclave, washer, chromatography skid, …)?
  • Does your system supply critical and non-critical systems (Clean compressed air vs. instrument air)?

Here are a few best practices and tips to make the decision process easier if they are not predefined on P&IDs:

  • For utilities, use the last valve prior to the system being supplied and include that valve as part of the supply utility.  This valve could be used as a Lock Out Tag Out (LOTO) point for that utility.
  • For skids and packages systems, you can use the advice above, or use the physical connections to the system such as tri-clamp connections or flanges,
  • For critical/non-critical systems, like air or HVAC systems, use the filter as your boundary between systems. 

Though there are many ways to approach and define system boundaries, we hope this will give you a few ideas on how to approach them. 

Article by: Tim Johnson, Managing Consultant, ICQ Consultants Corp.