Finally, that minor typo in Chapter 9 has been fixed; it has been a frustrating 10 years! Now that’s off my chest, we can look at the main changes between PIC/S GMP PE 009 version 13 and 14.
Usually, version changes have been restricted solely to chapters or annexes that are under review, however, given that small typo corrections were also made in this version, it made me suspicious of any other minor changes which could also be present. Careful examination showed no further changes outside of Chapters 3, 5 and 8, and of course, Annex 17, which leaves us free to discuss the major changes.
Like most industry professionals, I have followed the EU GMP changes with the mindset that they will eventually roll down to PIC/S within a year or two. However, it is curious that Chapters 3, 5 and 8 were released in the EU GMP March 2015, and it has taken a substantial amount of time afterwards to come to a consensus within PIC/S. I find the logic in new guidance incredibly helpful and practical – especially with the pulling back of toxicological assessments to a more sensible risk-based rationale reserved for potent drugs only.
So into the detail of the changes –
Chapter 3 Premises and Equipment
Clause 3.6 has largely been re-written and focuses much more on risk and risk management – specifically the requirement for dedicated facilities.
Depending on the risk level of the product, dedicated facilities may be required for manufacturing a medicinal product when:
- the risk cannot be adequately controlled by operational and/ or technical measures
- scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta-lactams)
- relevant residue limits, derived from the toxicological evaluation.
Chapter 5 Production
Prevention of Cross-contamination in Production
Chapter 5 has been updated with significant changes to most of the clauses in the sections on cross-contamination and starting materials. There is also a new section on product shortage due to manufacturing constraints.
Clause 5.17 now allows non-medicinal products to be manufactured in areas, and with equipment, that has been used for the production of medicinal products (provided that appropriate cross-contamination measures are applied, and the non-medicinal product is not a poison or herbicide).
Clause 5.18 has changed from “the contamination of a starting material must be avoided” to “should be prevented“.
The hazardous contaminant examples have been taken out, with the clause now focusing more on the “nature of the contaminant and that of the product being contaminated.”
The new Clause 5.19 details how any risks of cross-contamination should be alleviated by the design of the premises and equipment used as well as supported by the relevant technical and organisational measures (examples are given in Clause 5.21).
The new Clause 5.20 mentions that a QRM process should be utilised to assess and control the cross-contamination risks presented by manufacturing activities and that incorporating product potency and toxicology is an important factor.
Clause 5.21 has many new technical and organisational examples for preventing cross-contamination.
Some of the new technical measure examples are:
- physical barrier systems as containment measures, e.g. isolators
- dedication of equipment. e.g. product contact parts, selected parts which are harder to clean (e.g. filters), maintenance tools, etc.
- single-use disposable technologies
- validated automatic clean in place systems.
Some of the new organisational examples are:
- cleaning verification to be used to support the effectiveness of the QRM approach for higher-risk products
- verification of cleaning of non-product contact surfaces and monitoring of air within the manufacturing area and/or adjoining areas to demonstrate effectiveness of control measures against airborne or mechanical contamination
- designing of cleaning processes for premises and equipment so that the cleaning processes themselves do not present a cross-contamination risk.
Clause 5.27 has been heavily expanded to cover the selection, qualification, approval and maintenance of suppliers of starting materials. There is now more emphasis placed on the risks associated with the starting materials.
Clause 5.28 has more focus on manufacturers getting suppliers to agree to the established quality requirements for the starting material as well as documenting “appropriate aspects of the production, testing and control” in a formal quality agreement or specification.
The new Clause 5.29 outlines requirements for the approval and maintenance of suppliers of active substances and excipients.
While requirements for active substances focus on supply chain traceability and conducting initial and periodic audits of suppliers, a Quality Risk Assessment is also recommended for the control of excipients and excipient suppliers.
Clause 5.30 has more emphasis placed on checking the documentation of delivered starting materials as well as documenting the checking process itself.
New clause 5.35 outlines manufacturers’ responsibilities for the testing of starting materials ( perform ID testing of each batch at minimum).
New clause 5.36 lists all the requirements for outsourcing the testing of starting materials.
New Section – Product Shortage Due to Manufacturing Constraints
The new Clause 5.71 states that manufacturers are obliged to report any constraints in their operations to the marketing authorisation holder if the constraint may result in the restriction of product supply.
Chapter 8 Complaints and Product Recall
This chapter has been largely re-written and expanded upon. It has three new sections: personnel and organisation, investigation and decision-making and root cause analysis, and corrective and preventative actions.
New Section – Personnel and Organisation
This new section focuses on:
- having personnel responsible for handling complaint and quality defect investigations
- these persons being independent of sales and marketing
- the use of inter-disciplinary teams
- documenting roles and responsibilities if central management is involved in complaint and quality defect handling.
Procedures for Handling and Investigating Complaints Including Possible Quality Defects.
The complaints section has been entirely re-written and now gives much more detail on the procedures that should be used to investigate complaints.
The new clauses in this section concentrate on:
- determining and documenting whether a complaint represents a quality defect
- having procedures in place to allow the investigation of a batch’s quality where an adverse event is suspected to have occurred
- the procedures required to conduct a quality defect investigation.
New Section – Investigating and Decision Making
This new section covers:
- the actions that need to take place when conducting a quality defect investigation
- the need for decisions to reflect the level of risk presented by the quality defect
- the reporting requirements for quality defects.
New Section – Root Cause Analysis and Corrective And Preventative Actions
This section outlines that a root cause analysis and CAPAs should be used during the investigation of a quality defect. Quality defect records should be reviewed and trend analyses performed to identify any specific or recurring problems.
Product Recalls and Other Potential Risk-reducing Actions
This section is easily double the size of the old recalls section and includes the following:
- the need to have procedures in place to conduct a recall or other risk-reducing actions
- recalling a product before the full extent of the quality defect is known, in order to protect the public
- making batch/product distribution records available to the persons conducting the recall
- guidance on the recall procedures for an Investigational Medicinal Product
- consulting the competent authority, determining the extent of the product recall and any impact the recall may have
- informing the competent authority if no recall action is required as the batch has expired
- informing the competent authority in advance of a recall, unless rapid risk-reducing actions are needed
- implementing market-specific risk-reducing actions.
- assessing the risk of a medicinal product shortage which has no other alternative
- the need to document and discuss reworking requirements with the relevant competent authority.
- reassessing the remaining shelf-life for the reworked batches
- suggestion to periodically evaluate the current arrangements in place for recalls and conducting mock-recalls
- other risk-reducing actions to consider, e.g. notifying healthcare providers about a potentially defective batch.
Annex 17 Real Time Release Testing and Parametric Release
This Annex has been entirely re-written and now includes a section on real time release testing which involves a combination of in-process monitoring and controls that feed into batch release (replacing end-product testing).
Real Time Release Testing (RTRT)
This new section outlines the requirements necessary to implement a RTRT strategy including:
- measurement and control of in-process material attributes and process predictors corresponding to finished product attributes
- the requirement for the material attributes and in-process controls used to be based on prior process knowledge
- QRM, including a full process related risk assessment
- change control program (to assess changes for any potential impact to product quality or reproducibility)
- control strategy (e.g. in-process controls, material attributes, process parameters, sampling plan, acceptance criteria, etc.)
- specific personnel training programs (product specific as well as RTRT)
- qualification and validation management (applied to in-line and on-line analytical methods and where sampling probes are placed)
- deviation/CAPA system
- contingency procedure in case of sensor/equipment failure
- periodic review/assessment program.
It should be noted that if the results from RTRT fail or are trending towards failure, end-product testing cannot be used to substitute RTRT. Any failure should be thoroughly investigated and considered in the batch release decision. Attributes controlled by RTRT should also still be included in the certificate of analysis for batches.
Parametric Release and Sterilisation
This section provides guidance on parametric release. It has largely been expanded on and covers the following:
- the application of parametric release on products sterilised in their final containers
- if the manufacturer is using this method, they are required to have a history of acceptable GMP compliance
- minimum requirements of a sterility assurance program
- guidance on risk management and risk assessment for parametric release
- the level of qualifications and experience required by personnel
- managing changes that impact sterility assurance
- developing a pre-sterilisation bio-burden monitoring program for the product and components to support parametric release.
- strategies used to minimise product bio-burden
- defining the time lag between dissolving the starting materials, product filtration and sterilisation for aqueous or microbiologically unstable products.
This section covers the sterilisation requirements needed for parametric release and includes:
- qualification and verification of both sterilisation equipment and monitoring devices
- periodic re-qualification of equipment and re-validation of processes
- appropriately measuring process parameters during sterilisation with specified standards and calibrated measuring devices
- critical process parameters established, defined and periodically reevaluated.
- routine monitoring of the steriliser
- sterilisation record
- once approved, parametric release should be used for batch release (finished product testing cannot be used to overrule non-compliant results from parametric release).
If you are interested in reading more, you may also be interested in the following blogs:
- PIC/S update to PE009 – version 14 on its way
- New Draft Annex 1 -PIC/S and EU finally arrives
- Pre-use Post Sterilisation Integrity Testing – PUPSIT
- PIC/S PE 009-16 update, Part 1 – changes to Annex 13