PharmOut – GMP and Validation Blog

PIC/S Interpretation of Annex 1 – Clarifying or Confusing? Pt 1

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:

1. 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.

1. 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.

Add comment January 16th, 2010

Annual product reviews: Where to start?

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.

Add comment January 14th, 2010

ISPE 2009 Australian Conference

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

Add comment July 4th, 2009