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Comparison of PIC/S PE009-13 and PE009-14

Introduction

The PIC/S Guide to Good Manufacturing Practice PE009-13 was published January 1, 2017.  Edition 14 was published on 1 July, 2018.

The TGA adopted version 13 of the guide in 2018 and “just given” notice that it intends to adopt the current version of the PIC/S Guide (PE009-14) by July 1st 2020.

So you know what changes, if any you need to make to be in compliance with PE009-14, what are the key differences between these two guidance documents?

According to the Revision History the following content was revised:

  • Chapter 3 – Premises and Equipment
  • Chapter 5 – Production
  • Chapter 8 (Part 1) – Complaints and Product Recall
  • Annex 17 – Parametric Release

Where possible I will compare the changes.  For wholesale rewrites, I will summarise the new content.

Chapter 3 – Premises and Equipment

Section 3.6 has been rewritten to categorically state that cross-contamination should be prevented for all products.  A risk based approach to using dedicated facilities is advised.  Specifically drawing attention to the various product classes such as cytotoxics, sensitising materials, hormones etc has been dropped.

I’d like to see a line break between the end pf 3.19 and the start of 3.20.

Chapter 5 – Production

Section 5.17 has been moved from General into Prevention of Cross-Contamination in Production and expanded.  A reference to Chapter 3 is included and attention is drawn to technical poisons.

Section 5.19 has been reworded and condensed.  Chapter 3 is referenced.

Section 5.20. has been greatly expanded to include a discussion of risk assessment.

A new section 5.21 has been added outlining Organisational and Technical measures to prevent cross contamination with regards to Quality Risk Management.  The information here comes from PE009-13’s section 5.19 and is more complete.

Section 5.22 is new and advises regular review section 5.17 to 5.21.

The sub chapters on Starting Materials, previously included Section 5.25 to 5.35.  These have been expanded and now comprise sections 5.27 to 5.39.  New guidelines relating to risk assessments and supporting evidence has been included.

Section 5.29 introduces information on the approval and maintenance of suppliers of active substances.

Section 5.33 (the old 5.30) drops reference to Chapter 6, Item 13 and states solely Chapter 6. Item 13 relates to sample container labelling in PE009-13 and 14.

Section 5.35 is new and discusses who is responsible for the testing of starting materials.

Section 5.36 is new and discusses the rationale for outsourcing.  Importantly, this needs to be documented and justified.

Section 5.32 now becomes section 5.37.

Section 5.42 under Processing Operations Intermediate and Bulk Products (previously 2.37) no longer has “validation “in bold.  I would suggest this in no way deemphasises the need for validation.

Section 5.45 in Packaging Materials (previously 5.40) has been reworded from the purchase of materials to the selection, qualification and maintenance of suppliers of such materials.

Section 5.53 (previously 5.48) now states attention should be given to “avoid and remove” rather than “avoiding and removing” contaminants.

Section 5.59 (previously 5.54) now has the five bullets numbers rather than alphabetised.

Section 5.7 (previously 5.65) has not changed with regards to return of product from the market.  The resale or recovery of such product can only be assessed by the Quality Control Department, so NOT the Quality Assurance Department.  Presumably the investigation would be conducted by QC representatives and ultimately signed off on by QA.

A new sub chapter Product Shortage due to Manufacturing Constraints has been included with a single section, 5.71 discussing the need to report this in a timely manner to the marketing authorisation holder (MAH) is there is going to be a restriction of supply.

Chapter 8 (Part 1) – Complaints and Product Recall

The entirety of Chapter 8 has been greatly expanded.  I recommend you read the updated guidance in detail.

Previously there were three sub chapters:

  • Principle
  • Complaints
  • Recalls

Now there are six:

  • Principle
  • Personnel and Organisation
  • Procedures for Handling and Investigating Complaints Including Possible Quality Defects
  • Investigation and Decision-Making
  • Root Cause Analysis and Corrective and Preventative Actions
  • Product Recalls and Other Potential Risk-Reducing Actions

Rather than compare version 13 to 14, I will summarise what is in the version 14 Chapter 8.

Chapter 8 – Principle Summary

The Principle has been greatly expanded.  CAPA is now spelled out and reference given to Chapter 1.  The need to inform the Competent Authorities in a timely manner has been added.  Information on what happens when activities are outsources has been added.

Chapter 8 – Personnel and Organisation Summary

Appropriately trained, experienced and independent (from sales and marketing authorisation, unless justified) personal need to be responsible for investigating product complaints and quality defect investigations.

Sufficient resources needs to be allocated to this and they need to be available for interaction with the Competent Authorities.

Everything needs to be documented.

Chapter 8 – Procedures for Handling and Investigating Complaints Including Possible Quality Defects Summary

Document everything.  Determine if the complaint is legitimate.  Procedures need to be in place to document how to run an investigation.  Section 8.9 details what points need addressing as part of the investigation.

Chapter 8 – Investigation and Decision-Making Summary

Document everything.  Consider examining related batches (and possibly) products.  Review previous defect reports.  Make decisions based on risk and do this in a timely manner.  Report quality defects to the Competent Authorities in a timely manner.

Chapter 8 – Root Cause Analysis and Corrective and Preventative Actions Summary

Where a root cause cannot be identified, hypothesise what it might be and address that. The effectiveness of CAPA needs to be monitored and assesses.  Quality defect records need to be reviewed and trends analysed.

Chapter 8 – Product Recalls and Other Potential Risk-Reducing Actions Summary

Document everything.  If the product is on the market, any return needs to be conducted as a recall and this needs to be conducted promptly and at the drop of a hat.  If the recall affects clinical trials, the ability to identify blinded product (if necessary).

Consider discussing with the Competent Authorities the extent of the recall and they need to be informed BEFORE the recall is initiated.

Recalled products need to be stored back on site separately to other batches.  The recalled batch needs to be reconciled to capture every vial, packet etc.

The recall procedure needs to be periodically evaluated for effectiveness.  Here you could incorporate mock recalls into your internal audit program.

Annex 17 – Real Time Release Testing and Parametric Release

Previously names Parametric Release and containing items 1.1 to 3.17 (not including the Glossary, the sections now comprise 1.1 to 4.18 with the Glossary now being Section 5 (previously 4).

I recommend you read the updated Annex in detail.

The old sections were:

  • Principle
  • Parametric Release
  • Parametric Release for Sterile Products
  • Glossary

The new sections are:

  • Principle
  • Scope
  • Real Time Release Testing (RTRT)
  • Parametric Release and Sterilisation
    • Sterilisation Process sub section 4.12 to 4.18
  • Glossary

Rather than compare version 13 to 14, I will summarise what is in the version 14 Annex 17.

Annex 17 Principle Summary

Reference to the European Organization for Quality and a need to comply with the basic requirements of GMP has been dropped.  Now it states that product must comply with their approved specifications and reference is made to the Pharmaceutical Quality System (PQS).

Annex 17 Scope Summary

The scope outlines the requirements for Real Time Release Testing.

Annex 17 Real Time Release Testing (RTRT) Summary

What RTRT entails is explained and advice is provided on designing a RTRT strategy.  The RTRT strategy needs to be incorporated into the PQS.  Reference to Part 1, Chaper 1 and Part II Chapter 2 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products is provided.  References to Annex 13 and 15 is also provided.

As well as controlling the process, manufacturers need to ensure a state of control in maintained.

Staff need specific training in RTRT.  Key personal need to be adequately experienced and have sufficient knowledge and understanding of RTRT.

Emphasis is given to qualification, validation and management.

All deviations or failures need to be thoroughly investigated and adverse trends identified and examined.

Where RTRT has been approved, that approach should be routine.

Annex 17 Parametric Release and Sterilisation Summary

Here the release of a batch that has been terminally sterilised is discussed.

A distinction between in process monitoring vs examining a terminally sterilised sample is given to draw attention to what end-product test here is capable of showing compared to in process testing.

A product cannot be moved to another container following terminal sterilisation.

This process can only be used with a suitable history of GMP compliance.

Everything needs to be documented and everyone needs to be appropriately qualified.

Change control is needed for changes.

Advice on bioburden testing is provided along with ways to reduce bio-burden in the product.  Hold time validation (or at least consideration) is alluded to.

Sterilisation Process 4.12-4.18.

Qualification and validation are deemed critical and periodic requalification and revalidation should be planned. (Make sure you do it, not just plan to do it!)  Routine monitoring is needed to show the sterilisation is effective.  The steriliser trace should show all conditions were met for the cycle.

Non-compliance cannot be overrules by a finished product passing the test for sterility.

Annex 17 Glossary Summary

Revamped so rather than two sections, “Parametric Release” and “Sterility Assurance System” the Glossary now comprises:

  • Control Strategy
  • Critical Process Parameters
  • Critical Quality Attributes
  • Parametric Release
  • Real time release testing
  • State of Control

Conclusion

Chapter 3 introduced a risk based approach to segregation of product classes/categories.

Chapter 5 presents a greater emphasis Quality Risk Management especially with the new 5.21 sub section.

Chapter 8 was greatly expanded to detail corrective and preventative action, who does what (and what department they should be from), the need to inform the Competent Authorities in a timely manner and to conduct risk assessments.

Annex 17 Real Time Release Testing and Parametric Release was overhauled with a large discussion of the ins and outs of this form or release.

In addition to determining what changes you may need to make, you should check to see that you comply with the sections of the guidance that have not been revised.  If you do not conduct such reviews regularly, I recommend doing this at least every year at a high level as part of your internal audit program.  I also recommend that you review the guidance when updating or reviewing your documentation.

Paul Yeatman BSc 07/05/2020

I also reproduced this discussion on LinkedIn.

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Book Review of “Eliminating the Gobbledygook” by Kathy Walsh

As one with a love for documentation and trying to communicate effectively and concisely, I bought a copy of Eliminating the Gobbledygook – Secrets to Writing Plain Language Procedures by Kathy Walsh.  I am pretty sure I worked alongside Kathy some years back on what was called the Documentation Effectiveness Project at Mayne so I was not expecting too many surprises as we both know our stuff.  The purpose of the book purchase was to refresh and update my knowledge of controlled document writing.  I figured I may as well review the book in the process.

I was unaware that Plain Writing was a movement  – I thought that was just how things were done.  It is certainly how I was trained to write technical documents.

Eliminating the Gobbledygook, Secrets to Writing Plain Language Procedures is structured logically and follows the following pattern for each chapter:

  • introduction
  • contents
  • summation
  • what comes next
  • review questions / points to ponder

This mirrors the way I was taught to train small groups.

There are three main sections to the book:

  • About plain language
  • Writing in plain language
  • Developing a plain language Quality Management System (QMS)

While reading the book, I made notes on how certain aspects could be applied to my blogging as well as my presentations.  It was comforting to note that in my current job as a technical support engineer, I use my writing skills to provide instructions primarily in an imperative style.  It was also nice to see the overall concepts of document writing presented in the book were familiar to me.  I was a little surprised that those with industry knowledge and technical witting skills are rare.  This is a skill-set of mine I will start emphasizing.

Reading Eliminating the Gobbledygook, Secrets to Writing Plain Language Procedures was quite easy, demonstrating Kathy applies her own rules to her writing: A well written document or book is easy and fast to read.  I knocked off part one in under a day of interrupted reading. Part 2 took me about a week of interrupted reading. Part 3 took an afternoon to complete.

Note: As I am familiar with the content, my reading and comprehension time may have been faster than a casual reader.

Controlled and managed documents were differentiated which is an important distinction to make when it comes to your QMS.

Much of the information is “chunked” into tables and bullet points, which reflects an acceptable way of writing a SOP or OI.

Document scoping and assessing impact was discussed.  I cannot explicitly remember doing that when I updated or wrote documents.  It may have been something I just did.  e.g. considering what other processes might be impacted, the training that might need to be developed or delivered and what other documents might need to be updated or references altered in.  In any event, scoping your changes and conducting an impact assessment is great advice.

Helpful tables listing key ideas and showing examples were provided throughout the book.

Chapter 11 directs the reader to consider the audience when using italics.  As a microbiologist,  my recommendation is to always use italics when naming microbes as it is the correct way of doing things.  This chapter also touches on style guides.   Having completed a Visual Communication diploma*, I agree that style guides should be specific to marketing and branding collateral  – the flashy documents.  Your controlled and managed documents should be utilitarian and to the point.

One section I liked and you could find valuable is the one titled Avoid Worthless Changes and Time wasting (pg146/214).  I am a big fan of being efficient and detest the seemingly endless review cycle that can form between the writing and verification stages.

There were a few typos.  That may look bad in a document talking about accurate documentation.  Having written and reviewed 100’s of documents, even after espousing my attention to detail I always find at least one typo.

Eliminating the Gobbledygook, Secrets to Writing Plain Language Procedures, will be a great addition to my reference library.  It could be for you too.

*When I completed my diploma, Visual Communication was called Graphic Design.

Review of Draft Standard: AS 2828.2 Health records, Part 2: Digitized health records

One way I keep myself up to date with developments within laboratories and related areas is by reviewing draft standards.  This keeps me appraised of the current state of affairs, keeps my documentation audit skills fresh and potentially allows me to contribute to the content of standards.  For this draft standard, I have some knowledge of IT and IT security so am able to critically review the draft standard and offer comment.

Notes: refer to the conditions for comment stated towards the beginning of the draft standard.

DR AS 2828.2 Health records, Part 2: Digitized health records Continue reading

Review of Draft Standard: AS 2243.2 Safety In Laboratories – Part 2: Chemical Aspects

One way I keep myself up to date with developments within laboratories and related areas is by reviewing draft standards.  This keeps me appraised of the current state of affairs, keeps my documentation audit skills fresh and potentially allows me to contribute to the content of standards.

Notes: refer to the conditions for comment stated towards the beginning of the draft standard.

Update 20190103: After proceeding to submit comments, I observed page numbers were required.  That is important to note for future reviews.  Page numbers added.

DR AS 2243.1 Safety In Laboratories – Part 2: Chemical Aspects Continue reading

Review of Draft Standard: AS 2243.1 Safety In Laboratories – Planning and Operational Aspects

One way I keep myself up to date with developments within laboratories and related areas is by reviewing draft standards.  This keeps me appraised of the current state of affairs, keeps my documentation audit skills fresh and potentially allows me to contribute to the content of standards.

Here I step through the draft standard making comments.  Where a comment is answered later in the standard, I go back to my original comment and make notes.  An uncommented comment is potentially worthy of becoming an official comment on the standard.

Update 20190103: page nubmers added.

Section 1 Continue reading

IMM3022 Immunocytochemical and Lectin Labelling of Acid Secreting Cells in the Stomach and Kidney

IMM3022 Immunocytochemical and Lectin Labelling of Acid Secreting Cells in the Stomach and Kidney

Paul Yeatman

Partner/s: Rachael Davies, Tanya De Jong, AnnalieseSampey, Adreana Lambrinakos, Anna Rentoulis, Steve Argirio, Spiros Foscolos.

Date: 24th August -> 5th October 1994.

Introduction

Certain organs in the body contain cells, which are involved in acid secretion. In the stomach such cells are called parietal cells and exist in gastric pits contained in the stomach body. (Diagram.1 and Diagram.2). In the kidney such cells are known as intercalated cells, and line the collecting ducts of the kidney. (Diagram.3 and Diagram.4) In both cases, a two-subunit ATP dependent (ATPase) proton pump controls the acid secretion. Continue reading

Science In Australia

There was an advert for a science communicator / project manager this week.  The twitter post said must love science (*tick*) and have skills (*tick*).  I checked it out.  The role was skewed towards science communication and requires someone with a history of producing media reports, blogging, liaison with the science industry etc.  Enthusiasm alone would not cut it, though it would make the role a challenge, and that’s what I’m here for – challenges.

One requirement was to be able to name at least 10 science organisations in Australia.  Hmm, thought I cannot do that.  That’s embarrassing.  So, here’s what I could name off the top of my head and then here’s what I could find using the great advertising machine known as Google.

Off the top of my head with lots of brain racking

  1. Australian Synchrotron – http://www.synchrotron.org.au/
  2. CSIRO – https://www.csiro.au/
  3. Australian Signals Directorate – https://www.asd.gov.au/ (actually intelligence, thought this was science, or science based)
  4. Walter and Eliza Hall Institute of Medical Research (WEHI) – https://www.wehi.edu.au/ (I should know more of these)
  5. Florey, aka the Howard Florey Institute – https://www.florey.edu.au/
  6. The Australian International Gravity Observatory – http://www.aigo.org.au/ Everyone who visits should do the solar system walk.  Pluto is so far away!  Take water.
  7. The Australian Telescope National Facility – http://www.atnf.csiro.au/ – technically CSIRO.
  8. The Australian Antarctic Division – http://www.antarctica.gov.au/
  9. The Australian Association for Microbiology – http://www.theasm.org.au/
  • CSL before it went private (so not counting it).
  • Many pharma companies (which I’m not going to count).
  • Museums (Canberra, Melbourne, Sydney) – do these count.  They should count.
  • I could name ScienceInPublic, as they posted the advert.  That would be cheating!
  • All our universities.  Again, cheating if I named them.

Nine’s not bad, though I should know at least 20.

Ones I needed to look up (shame on me)

After four, I felt I was scraping the bottom of the Google barrel.  I soon discovered that while many about pages may list the organisation name in the header meta, the names were missing from the body of the page.  I also found that in lots of articles about science produced by Australia, the organisation producing the science was not named. Not how you build brand recognition.

  1. Australian Science Communicators – http://www.asc.asn.au/
  2. Australian Academy of Science – https://www.science.org.au/ Tad worried I’d forgotten about them.  I remember them as the premier science outfit and I had an old photo ruler from here.
  3. Innovation and Science Australia (ISA) – https://www.innovation.gov.au/page/innovation-and-science-australia
  4. Great Barrier Reef Marine Park Authority – http://www.gbrmpa.gov.au/ – I knew something existed, but could not name it.
  5. Woodside Australian Science Project – www.wasp.edu.au/
  6. The Australian Academy of Technology and Engineering (ATSE) – https://www.atse.org.au/
  7. The Royal Institution of Australia – http://riaus.org.au/
  8. Australian National Centre for the Public Awareness of Science – http://cpas.anu.edu.au/ Perhaps needs to work harder?  Three Google pages down using “australian science” as my search term.
  9. The Terrestrial Ecosystem Research Network (TERN) – http://www.tern.org.au/
  10. Peter Doherty Institute for Infection and Immunity – https://www.doherty.edu.au/  Most disappointing I did not know this given I’ve an immunology degree!
  11. Australian Centre for Advanced Photovoltaics (ACAP) – http://www.acap.net.au/

Related to this, I could name lots of science Australia has produced or is working on.  The various inventions reportedly to come out of Australia, (Hills hoist, the ute, the stump jumper), stomach ulcers being caused by Helicobacter pylori, matter transport/Quantum entanglement, eradicating rats by using dogs from an Island off the coast of Warrnambool (awww, Oddball died in February.  I’ve also merged this with Macquarie Island where dogs were used to eat all the rabbits, rats and mice – Oddball was a fox eaterupperer), wi-fi (CSIRO), the joint US-Australian military research project called Hypersonic International Flight Research Experimentation (HIFiRE) testing hypersonic engines, the people developing organs in a petri dish, various cancer research and I’m sure I could come up with more.

On the topic of Australian science, have a read of Australia’s National Science Statement – 2017.  It states science means “Natural, physical and life sciences, including medical and health sciences, mathematics, engineering and technology‑related disciplines.”

That’s not a proper description.  Science is the methodical and rigorous study of phenomena to understand them and the application of such methods and results to produce things.  The results can be knowledge, TV’s, vaccines, better car tyre rubber, ducks that go woof, less harrowing cancer treatments, key hole surgery, the “discovery” that fat is turned to water and CO2 and expelled in order to lose weight – even if it is obvious, it needs proving.

Making sure I had some idea my above description in bold was more or less correct, I checked our a dictionary and it said “the intellectual and practical activity encompassing the systematic study of the structure and behaviour of the physical and natural world through observation and experiment.”  Yup – within acceptable error limits.

PIC/S Guide for Good Manufacturing Practice for Medicinal Products (2013)

From Jan 1, 2017, the PIC/S GMP guide for Medicinal Products V13 will be in effect.  In Australia, the TGA requires version 9 is used, though rumour has it, version 13’s going to be adopted soon.  If such proposals as this one, which is mainly concerned with herbal “medicine” from the Complimentary Healthcare Council are ratified, then all future PIC/s updates will automatically apply to Australian manufacture.  Something to keep an eye on.

Compliance wise adopting PICS/s 13 over 9 is  not too big as deal as the PIC/S guide is based on old ICH Q7A guidelines dating from August 2001 and the right and wrongs do not change much over time unless something major takes place.  What manufacturers will need to pay attention to are the changes between version 9 and 13, namely:

  • Chapter 1, 2, 4, 6 and 7 revised – Part 1
  • Annex 2, 6, 7, 11, 13, 14 and 15 revised
  • QRM principles in PIC/S GMP added – Part 2
Screen shot of PIC's news item

Screen shot of PIC’s news item

Link to guide. (possibly dead) – Google search will find it for you.

Based on the contents of V9, things to review:

  • Quality Management
  • Personnel
  • Documentation
  • Quality Control
  • Contract Manufacturing and analysis

You should already be in control of the above areas as otherwise, you’d be having and uncomfortable 3rd party audit experience.  The overall principles do not change, just the fine-print.

Annex 1 deals with the manufacture of sterile medicinal products, so not much impact to us there. If you are performing risk assessments and utilising ISO9001, QRM should already be familiar to you.