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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.

Question Regarding PIC/S PE009-14

The current GMPs in Australia adhere to the PIC/S Guide to Good Manufacturing Practice, (PE009-13). This guide was adopted by the TGA in 2018 and the TGA has “just given” notice that it intends to adopt the current version of the PIC/S Guide (PE009-14) by July 1st 2020.

The Question posed on LinkedIn:

I have read PIC/S guidelines, when I was working in Pharmaceutical company. Currently, I am not working in Pharmaceutical company. I would like to keep my knowledge updated about what’s new in regulatory guidelines in Pharmaceutical. Would you please let me know, where can I get copy of new PIC/S??

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What is Data Trending and How To Identify, Action and Report Trends

The following is an article I placed on LinkedIn and was written as part of my Developing My Writing While Helping Others series.

Paul Yeatman is a microbiologist with over 15 years’ experience in documentation, validation and running investigations in TGA and FDA regulated environments. He has a strong interest in process improvement, documentation, training and developing others. From 9-5 Paul investigates and solves software problems.  By night he works on his science chops.  He has an arty streak, runs several blogs and enjoys communicating his experiences and knowledge in arenas such as this.

What is Data Trending and How To Identify, Action and Report Trends

USP Chapter <1116> Microbiological Evaluation of Cleanrooms and other Controlled Environments requires viable environmental data be trended and examined.  Trends allow detection of drifts away from what is considered a controlled environment and can be used to tighten existing alert and action levels/limits.

A major goal of any production facility is to maintain consistency or a state of control.  Another major goal is to ensure the final product is what it is meant to be, free from defects and contamination.  Understanding trends is an important part of achieving this goal.

Examples outside of viable environmental monitoring are included so you get a better understanding of this topic.

What is Data?

Data, for the purposes of this discussion, is anything that can be measured and recorded.  Within a microbiology monitoring program, trends are typically colony forming unit counts and Genus, species recovery levels.

What Data Can Be Trended?

Anything that can be recorded in the form of a number or that can be classified can be trended.  A small selection follows:

  • Incidence of a specific genus and species of microbe
  • Microbe counts
  • Temperatures of cleanrooms
  • Out of Specification result incidence
  • Corrective And Preventative Action not being completed in the required time frame
  • Potency of stability samples
  • Time spent on tasks

Why Trend?

By plotting data and looking at it from afar, one can see what is happening with the data.  There could be a lot of noise in the data and large spikes such as those representing an out of specification result while the overall figures are steady, rising or falling.  A good trend for Viable Environmental Microbiology Monitoring would be down.  For an income or profit trend, seeing an upward trend is preferable.  Over summer, temperatures might be seen to be higher in filling rooms than in winter.  This might or might not represent a control issue.  In any event, the opposite of what is desired represents an opportunity to identify and implement corrective actions.

The Two Types of Trends

Long term trends

  • Initially, long term trends gathered over a minimum of 12 months are used to establish your base alert and action levels (tighter or in line with what the regulations require)
  • Nothing that is observed in a long term trend should be particularly surprising to the Quality Assurance Team. Spikes will have (or they SHOULD have) been investigated, actioned and reported on at the time. An auditor examining your trends will expect this and is likely to ask for the reports.
  • Long Term Trending Example

Adverse trends

  • Short or long term trends that indicate a loss of control is near.
  • Consecutive actions, always showing area in a state of alert, unwanted microbe species detected, “too many” alert level results in a small number of consecutive samples.
  • A LIMS system could be set up to automatically identify an adverse trend. If using a paper and pen system, the data review stage should identify an issue if not already escalated by those recording the data.
  • As for long term trends, an adverse trend needs investigation, actioning and reporting on.
  • Short term trends showing an adverse trend

Long Term Trends

  • A trend is a set of data that is moving (once the noise is factored out) consistently in one direction. Over the course of 12 months, where a state of control is maintained, the overall trend would be a flat line.   A loss of control would see the trend go one way.  Improvements in the state of control could see the trends go the other way.
  • I recommend trends be reported in a graph. This saves trawling through data looking for something out of place and use of a graph allows for easy trend determination.  You should also present the data in a summary table broken down into months.  If management (or an auditor) desired to dig deeper, access to the raw data, such as that in a batch record could be arranged and tends to be expected.
  • In the Viable Environmental Monitoring Program, a downward trend could be considered good. This trend could allow for the tightening up of alert and action limits.
  • If long term trends show a potential shift towards a loss of control, things should be investigated. If corrective action can be identified, it should be implemented and the effectiveness of this determined.
  • The absence of a trend might also represent a problem. If results were always within limits or zero that is seen as a red flag to an auditor as even with the best processes, operators will make errors and there will be outlier results.  A history of a zero count in a clean room might also indicate a poorly validated recovery process so that would need to be checked.

Adverse Trends

  • Adverse, or short term trends are those that show a marked deviation (or potential deviation) from the norm. This could be three results of increasing values in a row or even four results out of six that show movement away from what is the baseline.  As these trends are short term, it is best to examine your trends on, at most every quarter as looking for adverse trends in a production facility every 12 months is a big risk. Assuming the adverse trend did not snowball into a big problem before the trends were examined, needing to investigate 12 months of batches compared to 3 is a huge difference in time, money, recalled batches (in a really bad scenario) and consumer confidence.
  • A stability sample might show that efficacy is maintained for 12 months at fridge temperatures and in the 15th month present a sharp decline. If the product has a 12 month expiry, not a problem. A 36 month registered shelf life could indicate an issue with the batch.  If a potency drop off was seen over three consecutive time points with the overall trend heading towards an ineffective (or unacceptable) level of API efficacy within the shelf life of the product then this would be an adverse tend.
  • As part of a viable environmental monitoring program, a single alert result every once in a while can be expected. Three or more in close succession (or in the same area if sampling is rotated over shirts and batches) could indicate a shift from control and a contamination problem.  The same goes for recovering the same microbe over and over again.  That might represent a clean room contamination issue, a media contamination issue, a test contamination issue or something else – it is up to you to investigate and determine the cause and take steps to fix things.
  • An adverse trend needs to be investigated and corrected.

For both long term and adverse trends and in accordance with the established schedules, I recommend you present the trends within a report. You will need to discuss the results, state whether they are acceptable or not and whether or not corrective action was implemented and if that was effective. You will need to reference the relevant reports. The trending report should be signed off by the head of quality and filed for quick retrieval. In the event that an adverse trend was identified, actions taken would be in accordance to established procedures. Relevant reports should be referenced in the trending summary.

Audit Considerations

Again, all adverse trends must be investigated, actioned and reported on. The Quality Assurance department, its internal auditors and third party auditors all expect this.

Your regular trending reports should point out any trends that are adverse or that represent a drift outside your state of control along with references to the reports that were written and the conclusions contained within.  Out of Specification results shown in the data should also be linked to their investigative reports. Not highlighting a drift away from control or an adverse trend could be seen concealment by an auditor.

If you use a computerised system to record your data or to produce your trends, you will need to demonstrate these systems are validated and potentially provide an IQ, OQ, PQ to the auditor(s).  You will also need to prove that data is unadulterated and that the figures presented are the figures originally entered into the system.

Conclusion

Anything that can be recorded can be trended.  By examining trends, long term and adverse trends can be identified and corrective action taken if necessary.  It is a regulatory requirement to trend your data and auditors will want to see the trends. Any “bad” trends must be investigated, actioned and reported on.

References

  • USP Chapter <1116> Microbiological Evaluation of Cleanrooms and other Controlled Environments
  • Title 21 CFR Part 11
  • PIC/S PE009-14 GMP Guide (Part I: Basic Requirements for Medicinal Products) 2018

 

Question regarding Bacillus subtilis recovery when testing for absence of Salmonella sp.

The Question posed on LinkedIn:

Dear experts, During microbial contamination testing for specific organisms – salmonella growing was observed. identification shows that is not Salmonella, but Bacillus subtilis. How i shoud interprated the results, pass specification or not?

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Controlled Documentation. Identifying what goes into a Policy, a SOP and an OI

The following is an article I placed on LinkedIn and was written as part of my Developing My Writing While Helping Others series.

I am a microbiologist with over 15 years’ experience in the pharmaceutical realm.  I have a strong interest in regulatory compliance, documentation and developing others.  Recently I have been working closely with data security.  I have an arty streak, have developed and delivered training and have an affinity for computers.  I ride bicycles…a lot.

Controlled Documentation.  Identifying what goes into a Policy, a SOP and an OI

Introduction

Within a regulated environment, there are multiple levels of documentation.  The purpose of such documentation is to ensure work is carried out in a legal, regulatory complaint and consistent manner.  These documents must be clear, not open to interpretation and justified in their content.  There are three levels of controlled documentation.  Policies, Standard Operating Procedures (Procedures) and Operator (or work) Instructions.  Each type of document serves a specific purpose and needs to contain relevant information.  Here I discuss the three levels of documentation and identify the purpose of each and the information each should contain.

The Three Types of Documentation

Within a controlled documentation system, a hierarchy of documents is advantageous.  In the companies I have worked for, there have typically been three.  Policies, Standard Operating Procedures and Operator (or work) Instructions.  Each document has a specific purpose and contains specific information.

The Policy

A high level document that generalises what goes on.   These documents contain regulator information (or references to the information), internal polices, rules and principles and why they are in place.

The Standard Operating Procedure (SOP)

This document describes overarching areas, such as Bacteriology, the Viable Environmental Monitoring Program, Site Validation, and Sterility Testing.

A SOP details a series of tasks that takes place over time with an identifiable goal.

As an example, a bacteriology SOP would bring together everything to do with this subject including plating, identification, maintaining a culture collection with the aim (perhaps) to allow staff to identify and maintain microbes.

The language in this document should be clear and not open to interpretation.

The Operator Instruction (OI)

This is the lowest level of documentation and describes a specific process that usually can fit on a page or two and has a specified outcome.  Examples based on the subjects listed in the SOP section above include for Bacteriology: Perform a Gram Stain, for the Viable Environmental Monitoring Program: Operation of the MAS100 Air Sampler, for Site Validation: Validate A New Incubator and for Sterility Testing:  Sanitise the Isolator with Hydrogen Peroxide.

Using the Perform a Gram Stain example, this would detail the step by step process for taking a colony off a plate and staining it using the Gram stain method.

What Information goes in each document

A policy explains the reasons behind a process.

A SOP provides the who, what, where when and order of something. If a process takes more than a day (generally) then a SOP is the appropriate document to write.  A SOP might be used by more than one person at a time.

An OI is more time limited than a SOP and the task the OI details is normally conducted by a single person at a time.  Steps that may be generalised in a SOP are specifically stated within a OI.  Do this.  Do that.  Do this other thing.

Document Structure

Like any well planned writing, a logical structure is important.  All documents should have a header and footer containing such information as writer, verifier and approver, approval and expiry dates, document number, title, page number and total pages.

A policy could be set out as follows:

Purpose, Background, Roles and Responsibilities, Overview, Listing of related polices, Glossary, References.

A SOP could be set out as follows:

Purpose, Who uses the policy, EHS considerations, Before you begin, Procedure, Additional information, Glossary, References.

An OI could be set out as follows:

Purpose, Who uses the OI, Before you begin, Overview, Instructions.

Other Considerations

Templates

Useful for providing consistency of format and providing examples of acceptable content. A template ensures consistent document structure and formatting of titles, headings, body and table content.

Scheduling and Planning

Used alongside document validity dates.  Enable the documentation controller and users to proactively schedule document review and update. Planning is important so the document is updated without rushing (i.e. the week before it is due to expire).

Who Writes the Documents

The subject matter expert (SME) is the best writer.  Don’t be afraid of delegation however. A technical writer can be used provided the document is written in consultation with the SME.

Who Reviews and Approves Documents

The reviewer should be a peer or someone in the management chain for the writer as they should also have knowledge of the process being documented.  The reviewer looks for content accuracy, correct grammar and correct references.  Ideally, the writer does the review and a verifier is used to confirm the work of the reviewer.  This reduces work for both the writer and the verifier as the document does not have to keep going back and forth between the two.

The Approver will ideally be the manager of the department responsible for the process being documented.

Change History

It is very important to track changes and document the reasoning behind changes.  Helps an auditor to identify and approve changes.  In my view, this section can never contain too much information.

Training

Staff need to be trained to follow SOP’s and OI’s and when a significant change to a SOP or OI is made, your staff need to be trained in the changes.

Standard Procedure for Documents

In order to produce consistent documentation with sensible content in a consistent format, procedure for doing this is helpful and within a regulated environment, a necessity.

Conclusion

You will now be familiar with the three main types of controlled documents: Polices, SOPs and OI’s, when they are suitable for use and what sort of information each type of document should contain.

 Appendix

Summary table of the types of information that goes into a SOP and an OI