Posts filed under 'Compliance'
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.
Remarkably, the Annex provides no definition of “Grade A” air supply, making the interpretation even more difficult. Thankfully, the revision of the PIC/S interpretation (PI032-2), defines a Grade A air supply as:
“a supply of air which is HEPA filtered, and at the point of supply meets when tested, the non-viable particulate requirements of a grade A area, as defined in paragraph 4 of the revised Annex 1.”
Additionally, it provides qualification and monitoring requirements for such areas:
· Qualified “at-rest” only. No requirement for “in-operation” qualification
· Qualification requires non-viable counts only
· Particle counts to be conducted “at the point of supply of the filtered air”
· Unidirectional (laminar) air flow is not required, but smoke tests should demonstrate absence of air entrainment from surrounds
· Air velocity limits should be justified (but don’t need to meet Grade A conditions)
· Monitoring for both viable and non-viables should be defined through risk assessment.
The wording of the interpretation refers to transfer tunnels, and it is clear that most, if not all of the thinking for this subject has focussed on this type of arrangement.
So that still leaves the issue “what does this requirement mean for (for example) a small company who transfers fully stoppered vials from an aseptic filling station to a “clean” capping station manually?
Well, on review, it turns out that Grade A air supply is perhaps not as big an issue as it may have seemed. Applying the definition and qualification requirements, it seems clear that any well designed Grade B zone (and probably most Grade C zones) will meet the requirements of a Grade A air supply! Remember, Grade B non-viables limits at rest are almost identical to Grade A.
So don’t panic, you may not need to spend thousands of dollars upgrading air systems after all. Having said that, there are still two significant implications which manufacturers need to consider.
· Have you fully validated your stoppering process so that you can be confident that 100% of your vials are fully stoppered? If you cannot be certain that every vial coming out of your aseptic area is fully stoppered, you are likely to require not only grade A air supply, but fully Grade A and aseptic conditions until the completion of crimping.
· And whatever your transfer process, you need to be able to prove that it does not pose additional risk to your products, so the method of transfer will come into question just as much as the environment in which it is conducted.
Now, transferring a tray full of stoppered vials through a Grade B area from filling to capping; that seems like an excellent candidate for Grade B continuous monitoring … but that’s another blog!
February 4th, 2010
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.
- In section 12 the Annex confirms that sample sizes for monitoring do not need to be the same as for classification. The PI 032 interpretation quite rightly points out that needing to sample a full cubic metre before activating an alarm is problematic, especially in Grade A zones. The implication, of course, is that significantly smaller sample sizes are appropriate where fast response is required.
With that in mind, the use of the phrase “sampling of 1 m3 … could be inadequate” is potentially misleading, insofar as the word “inadequate” implies not enough, when really it is too much. A more suitable term to avoid confusion would have been “inappropriate”.
- The inconsistency between sections 34 and 116 was raised in part 2 of this article. If you are unsure about which section to follow, obviously the safer and more advisable route is to stick to section 116 and avoid the use of sealed transfer trays.
In itself this issue is barely worth mentioning, but with PI 032 implying that section 12 is now superseded, it seems that the carryover of section 34 has not been noticed by the reviewers or interpreters.
Additionally, the interpretation states that section 116 is “basically equivalent” to the old section 12, yet there is a very important distinction. There is no provision in the new section for transfer in sealed containers, and it would be impossible to meet this stated requirement using sealed containers, as Grade A airflows cannot be met.
- On a positive note, I should mention that I had some issues with the PI 032 interpretation of clause 121, however, the revision PI 032-2 has largely addressed those concerns. Originally the document could be interpreted to suggest that you could mitigate an ineffective rejection system by improving the quality of the background environment. The revision clarified these comments to put the emphasis on monitoring and the degree of human intervention required in the rejection system.
Finally, it should be noted that there are 20 or so interpretations in the PIC/S recommendation and I have highlighted 4 or 5 which I think could be reworked to varying degrees. The remainder generally provide sound advice, clarity and definitions that the user can employ with confidence.
However, the issues raised should be addressed by PIC/S – especially those covered in parts 1 and 2 of this article. Given that PIC/S was prepared to issue version 2 only a month after version 1, let’s hope that version 3 may not be too far away.PIC/S Interpretation of Annex 1 – Clarifying or Confusing? Pt 2
January 18th, 2010
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:
- The requirement for Grade A air supply has presumably come about because uncapped vials are considered non-integral, and therefore potentially at risk of being contaminated. Grade A air supply rather than “Grade A conditions” have been specified, perhaps because of the difficulty and expense in installing, maintaining and qualifying such systems couldn’t be justified in light of the risk. Even so, a risk has been identified and measures provided to mitigate that risk.
With this is mind, why would the interpretation advocate the use of unsterilized caps on these non-integral vials? Yes, it’s understood that the process at this stage is not aseptic, but after having deemed the risk high enough to mandate that manufacturers spend many thousands of dollars on maximising air quality, why is PI 032 prepared to expose these same ‘non-integral’ vials to potential contamination from unsterilized caps?
- Another area of confusion is related more to the Annex than the interpretation. section 34 states that partially stoppered vials may be transferred to a freeze dryer either under GradeA conditions, or in sealed transfer trays in a Grade B environment. section116 covers the same topic, but omits the sealed transfer trays. section 120, on the transfer of fully stoppered vials to a capping station also does not provide scope for transfer in sealed trays.
If these sections are taken at their word, the Annex allows the transfer of partially stoppered vials in sealed transfer trays, but does not allow the same for fully stoppered vials. Logically, this doesn’t make sense. (The section 34/116 inconsistency is discussed further in part 3)
To sum up, I would expect that caps on aseptically filled vials would be sterilised before introduction into the capping process, regardless of whether the process is truly aseptic, or simply ‘clean’. The impost of sending a bag through the autoclave is surely next to nothing compared with that of complying with the environmental requirements of the Annex, but maintains a consistent approach to protection of ‘non-integral’ vials.
Similarly, despite the retention of section 34, it seems clear that the intention of the guide is to move manufacturers away from sealed containers and I would recommend against their use. It would surprise to see section 34 modified or removed from future revisions.
The final part of this article will discuss some minor issues in the interpretation.
January 18th, 2010
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?
In my opinion, while the revision has provided some modest improvements in clarity and added one or two useful pieces of information, there are still a number of areas for concern. There are statements within the interpretation that, rather than providing clarity, create more confusion for manufacturers. In both the original version and the revision, there are two interpretations which I find particularly confusing.
In this first part of the article I will address the most critical issue, which relates to section 10 of Annex 1. The text states (emphasis and comment added):
“It is recommended that a similar system (to that employed for Grade A zones) be used for Grade B zones although the sample frequency may be decreased. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.”
The PI 032 interpretation states in full:
“Continuous monitoring (see definition under interpretation to section 9) is expected while not fully integral containers are handled in the B zone, e.g. partially stoppered vials within a laminar air flow mobile unit prior to lyophilisation. Manifold systems might not be suitable for Grade B Zone monitoring due to a lack in responsiveness.”
I see at least 2 problems with this interpretation:
- PI 032 applies the same definition for continuous monitoring for both Grade A and B zones (a system which is able to pick up ANY potentially occurring event of an unusual number of particles). Interestingly, the term “continuous monitoring” is not used anywhere within Annex 1, least of all in the relevant sections 9 and 10. The definition described in PI 032 most closely matches the description of the monitoring requirements of Grade A zones, BUT Annex 1 clearly differentiates between monitoring requirements for Grade A and B.
- Grade A: The grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded
- Grade B: The grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.
My interpretation of the differences here is that Grade B monitoring need not capture every single unusual event, but rather be able to detect system deterioration and or gross change in contamination levels. Surely if the intention of the code was that every single spike must be captured, terminology much more akin to the Grade A definition would have been applied.
I believe those interpreting Annex 1 have erred in suggesting that monitoring for Grade A and for Grade B environments can be grouped together like this. In my opinion, continuous monitoring in Grade A and Grade B zones is NOT intended to be the same.
- PI 032 states “Continuous monitoring … is expected while not fully integral containers are handled in the B zone”. Given the absence of any other information, this implies that this is the only condition under which “continuous” monitoring is required in B zones. Having understood and accepted the term “continuous monitoring”. I find this interpretation quite strange for the following reasons:
- Firstly, Annex 1 provides no direction on what activities should be monitored in Grade B areas. The only concession given is that the effectiveness of segregation between Grade A and B zones should determine the importance of the particle monitoring. Surely PI 032 goes beyond interpretation to place a specific condition which cannot possibly be inferred from Annex 1 itself.
- Secondly, what exactly does “while not fully integral containers are handled within the B zone” mean? PI 032 gives an example of partially stoppered vials within a mobile laminar flow (must be Grade A according to section 116), but how is that being “handled within the B zone” anymore than vials being processed within a fixed laminar flow? There are more questions here, but the confusion is evident.
In trying to reconcile why PIC/S have published this interpretation of section 10, I wonder if they have just been too brief, omitting important additional information, or perhaps they have misinterpreted the intent of the original text. To me, the text appears to require monitoring of Grade B environments for the duration of aseptic and other critical processes (continuous, if you like), albeit at a reduced sampling frequency from Grade A monitoring. But this is not what the interpretation says.
We need further elaboration from PIC/S on this subject to remove the confusion.
Part 2 of this article will deal with concerns about section 120.
January 16th, 2010
PharmOut has available a white paper on the recent TGA update to the Guide to Good manufacturing principles PE009-08 (effective in July 1st, 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 1st, 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.
January 14th, 2010
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.
January 8th, 2010
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.
January 6th, 2010
You have to go to the ISPE Conference in Sydney, I will be presenting on cost effective quality management systems, yes those SOP documents that control your business processes. So often people forget that pharmaceutical document systems are simply written representation of their processes and introduce loads of cost layers in trying to be TGA compliant – unneccessarily
However, if you are not convinced, we have leading international speakers from Medsafe, TGA, PIC/S and many industry experts. You can ask them all your tricky compliance issues and GMP questions.
Click here if you are interested – www.ispe.org.au
July 4th, 2009