PharmOut - GMP and Validation Blog

After my recent three part blog on the PIC/S interpretation of Annex 1, I’ve had reason to revisit the recommendation at some length. During this process I had a moment of clarity regarding capping environments that had escaped me previously.

Section 120 of the Annex states that capping can be performed as either an aseptic process, or as a clean process outside the aseptic core. However, if uncapped vials are to be removed from the aseptic core, the Annex specifies that a “Grade A air supply” must be maintained until the vials are capped.

While the original intention for this section undoubtedly was in consideration of transfer tunnels and similar apparatus which connect the aseptic core to a separate capping area, it starts to become ambiguous when applied to transfer by hand or on open conveyers. Read the rest of this entry »

This is the final part of a three part article on the new PIC/S Recommendation (PI 032).  The Recommendation interprets the changes to Annex 1 of the PIC/S GMP Guide. In this part, we look a few minor issues arising from the publication.

There are a few other points in the interpretation which I feel have the potential to cause confusion. These aren’t so significant, but warrant a mention to raise awareness. Read the rest of this entry »

Following on from my previous blog entry, this article looks at a second significant issue with the PIC/S Recommendation (PI-032) which interprets the changes to Annex 1 of the PIC/S GMP Guide.

The second, less critical issue I have relates to section 120 on capping environments. The Annex states that capping can be performed as either an aseptic process, or as a clean process outside the aseptic core. However, if uncapped vials are to be removed from the aseptic core, the Annex specifies that a “Grade A air supply” must be maintained until the vials are capped. The definition of Grade A air supply has been helpfully clarified in the revision of PI 032.

While this requirement no doubt creates a significant cost impost for new facilities and where the requirement is currently not met, the reasons for it are understandable. There are, however, two areas for concern: Read the rest of this entry »

This is the first part of a three part article critiquing the new PIC/S Recommendation on Annex 1 of the PIC/S GMP Guide.

Last month, the PIC/S committee released their interpretation of the 2008 changes to the GMP Guide Annex 1 (manufacture of sterile medicines). This document, PI 032-1, was agreed by PIC/S in November last year after a committee meeting in Uppsala, Sweden. Following some apparent concerns about the publication, a revision (PI 032-2) was published on January 8, 2010. But if the original document had issues, has the revision addressed them all? Read the rest of this entry »

PharmOut has available a white paper on the recent TGA update to the Guide to Good manufacturing principles PE009-08 (effective in July 1^st, 2010).

www.pharmout.com.au/downloads/white_paper_tga_gmp_updates.pdf . Below is the extract on Product Quality Review.

“The new code includes product quality reviews—while companies with experience in FDA Compliance will be familiar with these, this is the first time that the TGA has required such reviews. Product quality reviews will need to be performed annually for all licensed medicinal products (including export only products). The new code includes prescriptive details of the review requirements.

Reviews, as a minimum, must consider starting materials (including packaging), in process and finished product results, batch failures, significant deviations, changes to process and analytical methods, marketing authorisation variations, stability results, complaints and recalls, corrective actions, post-marketing commitments, equipment qualification status and contractual arrangements (for contract manufacturers).It is also expected that each review is evaluated and assessments made on need (or otherwise) for corrective and preventative action, including re-validation. Allowance is given for the grouping of reviews by product type (e.g. solid dose, sterile, etc.) where ‘scientifically justified’. It should be understood, however, that each individual licensed product must be reviewed and assessed fully, even when part of a grouped report.”

Great, this is another quality process that needs to be introduced. What the code does not tell you is how to do the reviews, the fine detail or individual parameters to assess. This has been left up to each company to develop. What can be clearly seen is that it is not a simple task that can be completed by an employee to fill in “some time”. This is a significant exercise that will require planned activities, documented procedures, templates for recording information and finally a process of evaluation the information gathered. (Some statistical analysis will be required).

Ultimately this is another step of development in the “continuous improvement” or “life cycle” of product, the path the regulations are moving in. Industry to remain compliant, must follow. What product reviews force you to do is, understand the performance of your process and your product. It provides you direction to monitor and improve your processes of manufacture and product, rather than accepting the issues that you may routinely encounter. It is another process to drive you to stay current and compliant.

So after a period of time you develop the processes, the documentation and the resource to complete the annual product review.  “Great, now can I have all my products completed by July 1^st, 2010 ? It just can’t be done. !!!

Well, this will be a true statement for many manufacturers. What do you do ? You know it’s impossible ! The simple answer is, you must create an action plan, identifying your products and product range, and create a reasonable timeline to address the annual product reviews for your products. You must be able to show an auditor that, you have;

1)    identified what is required to perform the tasks

2)    created the necessary documented process to perform the task and

3)    created a reasonable plan,  with timeline, to address the outstanding activities.

Once established, your are well on the way to having a controlled and compliant process to address Annual Product Reviews.

Businesses are always looking for opportunities to expand their portfolios to manufacture product for the commercial market. Whether you are a major or small player in the parenteral injectable market, there are increased commercial opportunities if you can have your facility regulatory approved to manufacture product aseptically.

Being able to manufacture product that is terminally sterilised, in its final container to ensure the sterility provides the foundation for the transition to an aseptic filling manufacturing facility. But there is significant cost and effort (in both documentation and activity) that an organisation will face to make that transition. Additionally, there is new expertise that must be developed and maintained within the organisation.

Taking the simplest option of non sterile components/materials being appropriately processed and sterilised and then combined aseptically, many aspects must align to ensure a sterile product in the final container. The list below provides some initial guidance on what the transition to aseptic processing will require:

1.    Change in the design of the clean rooms and processes flows must be assessed, as the changes can be significant.

2.    Higher level of classification of the clean room environment, with more stringent performance criteria to be met and maintained.

3.    Increased number of validation studies required to assure processes and equipment are under control.

4.    Increased level of ongoing testing and monitoring of the clean room facility and services.

5.    Processes and procedures to perform media fills, and an understanding of the required actions based on the results obtained.

6.    Greater knowledge of aseptic/microbiological aspects to the manufacture by all staff working in the manufacturing facility, this includes cleaners, maintenance crew, laboratory, validation and manufacturing personnel.

7.    An increased level of oversight by knowledgeable, experienced individuals in aseptic manufacture, to develop the staff in the correct activities required to produce aseptically filled product.

Once you have convinced regulatory bodies like the TGA and FDA, through the completion of a successful audit, the company must factor the increased running costs of a facility to maintain this higher risk level of manufacturing capability.

Ongoing media fills, increased level of environmental monitoring of the facility and personnel, the need for much greater interaction between manufacturing and QA\QC (especially when manufacturing issues occur during filling), the microbiological and sterility assurance knowledge and the list goes on. With the increased activity, there is an increase in staff numbers that will be required to maintain the facility in a compliant state.

Finally, as aseptic manufacture is regarded and rated as a high risk process to manufacture sterile product, there will be an increased level of regulatory auditing.

John Montalto is training in Singapore at the moment, he is an excellent trainer, very energetic and engaging.

Your company has just been audited, by a regulatory body like the TGA or FDA, a supplier or manufacturer, and they found the “obvious issues”. The company has too many open or unfinished deviations, corrective actions, change controls and customer complaints. You have a list of other observations presented to the company by the auditors. Now the company must act!

There are so many outstanding issues but product must be made and product must still be released to market. The focus to close these issues just does not seem to be there.  To state the obvious, the priority has to changed, as the issues won’t fix themselves.

So where do you start!

This IS a COMPANY issue, and it will require a COMPANY solution to remediate the situation. It will take several keys actions to address the issues:

1.    Senior management acceptance of the situation and its impact on the business.

2.    creation an action plan to address the issues

3.    Having a key responsible person to drive, monitor and communicate progress of the action plan. (Project leader)

4.    a small focused team, who will allocate a portion of their time to addressing the issues and

5.    Starting……….

The key to success is understanding that the benefits are

1.    addressing the issues identified by the auditors, therefore regulatory or site compliance

2.     grouping of similar issues, so that they can be addressed effectively and efficiently,

3.    By addressing the issues you can identify trends, or opportunities that will save, time, money, double handling and create a greater benefit to the company.

The process must be monitored and reported to the key stakeholders on a regular basis. The monitoring will provide the measure of success to the action plan.

There are many companies in similar situations to your own. So don’t feel alone. I have seen and have been involved with companies, in the situation described above. The resolution did not occur over night. It took time, focus, energy, commitment and leadership.

The benefits are obvious. The list is down to a manageable and acceptable level. The system of addressing the issues is more efficient and timely, and people have accepted that they all have some role to play from time to time to support the ongoing maintenance of the systems. Importantly, the auditors (who will be back again), can see that your key systems are back in control.

An interesting press release was issued by PIC/S last month, commenting on the results of a PIC/S assessment team visit to the FDA: ” more progress was achieved during these
two weeks than during the previous three years of assessment. The team assessed the US GMP inspection system and also observed inspections carried out by FDA inspectors. It also met with FDA Commissioner, Dr. Margaret Hamburg, who stated that PIC/S membership was a top priority for the FDA.”!

This is exciting news for pharmaceutical and medical device manufacturers who must comply with multiple regional regulations and country-specific regulations. At long last, there may be an end in sight to the wasting of valuable time and resources in complying with multiple regulations rather than building quality and patient safety into the product. A global GMP standard may actually be achieved in my lifetime!

Whilst it’s great news that the FDA is moving closer to PIC/S membership, it would be a real shame they throw out all their regulations / guidance documents in the process. For example the draft “Process Validation Guidance” issued by the FDA last year provides a refreshing look at product development, commissioning and control. It outlines a whole life cycle development approach to product quality and risk management. So much better than the old three golden batches, how can three consecutive batch “prove” that your process is control! If the FDA does become a PIC/S member, I hope that PIC/S can pick up the best of the FDA’s work and integrate it into their own regulations and guidance documents.

It is interesting to note that there are now thirty seven PIC/S member countries. The membership applications of Indonesia / NADFC, Slovenia / JAZMP and Thailand’s FDA were recently reviewed, potentially expanding the number further. The next assessment for membership will be Latvia’s State Agency of Medicines (ZVA).

This is the first PharmOut training blog. Hopefully there will be many more, please post your questions and comments here.