Editorial and PHSS News

Editorial (Guest)
By Guest Malcolm Holmes, PHSS Pharmaceutical Regulatory SME

It’s what we do

In the Pharmaceutical industry we discover new molecules with a potential to be used as medicines. Then we commence the long journey to turn that discovery into safe and effective medicines. All the time we should strive to gather knowledge which helps us understand and improve our products and processes, to ensure that the resultant medicines remain safe, effective and available to healthcare professional and patients.


But there are hurdles to overcome

Manufacturing issues leading to shortages


When a medicine becomes not available it is consequently of no use to the patient. From time to time firms experience manufacturing issues which can cause them to restrict or cease supply of a medicine until such issues are resolved. Regulators have in recent years placed a significant focus on need for reporting such shortages caused by such manufacturing issues and then steps being taken to alleviate the shortage as well as to prevent it happening in the future.


Product recalls arising from previously unknown product and process issues


Where a medicine is found to be sub-standard a common outcome following risk-based discussions between regulators and manufacturers is a product recall. Usually such events involve an individual batch or specific batches of a product which may be implicated. From time to time however the impact is much wider. For example, in 2007 it was noted that tablets of an antiviral drug VIRACEPT® (nelfinavir mesylate) exhibited a bad odour. This odour arose from ethyl mesylate – a genotoxic chemical. Product was recalled world-wide and the product authorisation in the EU was withdrawn by EMA and not reinstated until October that year. The investigation into the cause of the contamination of the product concluded that it had been caused by a reaction between ethanol, used in a cleaning process which was left in a manufacturing vessel subsequently used to hold methanesulphonic acid. An event such as this was very rare indeed.


More recently, in the summer of 2018 a U.S. drug manufacturer told the US FDA that it had discovered the impurity N-nitrosodimethylamine (NDMA) in a valsartan active pharmaceutical ingredient made its Chinese API supplier. Subsequently the FDA found NDMA and a similar chemical, NDEA, had contaminated certain valsartan APIs for years. The agency said the two contaminants, (both probable carcinogens) can form through specific and commonly used manufacturing processes.


Regulators worldwide were alerted and conducted their own investigations as well as jointly with the USFDA. Similar problems were identified with other Sartans and then in recent weeks with Ranitidine products. Multiple batch recalls have been undertaken as precautionary measures. These products are commonly used medicines and are often taken over long time periods by patients thereby potentially increasing the risk of harm.


On 11 November 2019 EMA issued a Q&A document on “Information on nitrosamines for marketing authorisation holders”. This 12-point Q&A indicates that all marketing authorisation holders (MAHs) of all human medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) should work with the manufacturers of their APIs and finished products in order to evaluate the risk of nitrosamines being present in their products, and take appropriate risk mitigating measures.


A risk-based prioritisation of products to be reviewed should be used and the outcome of the risk evaluation of all products should be concluded at the latest within 6 months of the publication of the Q&A i.e. by 11 April 2020.


Section 12 of the Q&A covers currently identified root causes for presence of nitrosamines. In this section the EMA has highlighted the involvement of agents such as sodium nitrite, and recovered solvents, but also reported that the use of certain packaging materials may contribute to contamination. Section 12, Point 8 notes that “Nitrosamine contamination has been observed by one MAH in a finished product stored in blister” and “the MAH has hypothesised that the lidding foil containing nitrocellulose printing primer may react with amines in the printing ink to generate nitrosamines, which would be transferred to the product under certain packaging process conditions”.


Since that time Metformin tablets (used as a regular medicine for diabetes) have also been potentially implicated.

Next steps

Readers attention is drawn to the EMA Q&A document which is available on the EMA website and which should be urgently and carefully reviewed for scope, methodology and timelines. The timeline for compliance is short and the clock has been ticking since 11 Nov 2019.


Further information can be found in the Regulatory Updates in this and previous editions of EJPPS as well as on the PHSS and Regulators websites. PHSS has also issued two Impact Statements on this topic the first in May 2019 and most recently in Nov 2019.

PHSS News - Chair of The PHSS

Dear Readers


2019 has been an exciting year for PHSS, with many developments and changes, including a new chair!

We have been able to facilitate two outstanding conferences in June and September, together with the Aseptic Processing Workshop and QP Forum. Our focus remains on bringing the opportunity for industry discussion and engagement, by sharing knowledge, regulatory guidance and GMP practical guidance.

We have continued to focus on delivering practical guidance through our special interest groups, this will be maintained under James Drinkwater’s leadership as we go into 2020.

In September we launched the new look EJPPS. I am very proud that we are now able to bring the digital version to the industry. To view our latest edition please visit www.ejpps.online/


I would like to thank Tamsin Marshall, PHSS Operations Manager and Kay O’Hagan, EJPPS Editor in Chief for all the hard work, drive and dedication to deliver this new platform for the journal.

In 2019, we have been honoured to welcome some new faces joining our management committee as co-opted members, this has brought experience and diversity to enhance the PHSS team.

It is an honour to be able to step into the chair position, taking over from James Drinkwater after his 10 years in the post. James will, of course, continue to be very involved with the PHSS, staying on the management committee as well as leading the Aseptic Processing Special Interest Group (SIG). For more details on our 2019 Event and SIG summary please see the full update from James.

On behalf of the PHSS, I would like to wish you all the best wishes for the festive season.

Jenni Tranter, PHSS Chair

November 2019

PHSS Activities and initiatives EJPPS report December 2019

By James Drinkwater - Head of PHSS Aseptic processing and Containment Special interest group and Annex 1 Focus group.

PHSS QP Forum in Wales November 2019

This year the PHSS QP Forum was supported by the MHRA with a Key note presentation from Phillip Rose a senior GDMP Inspector. The program of presentations were high quality leading to a sold out event with the best ever attendance. To build on this success and transition from a discussion forum for QPs to a full conference the PHSS will introduce a new venue for 2020 will enhanced conferencing facilities.

PHSS initiative in preparation of Clarity on GMP Guidance notes

Focus groups are now formed for each of the Clarity on Guidance note topics with supporting scope and content for each topic prepared. Significant progress is expected in 2020 with a target to complete as many as possible by the annual Aseptic processing & Bio-contamination special interest group meeting the day before the Annual PHSS Challenges in Sterile product manufacturing conference in June, Manchester UK.

Current topics to be covered are:

1.Assurance of Sterility for Indirect product contact parts: Vial/ Syringe filling Stopper/ plug pathway. Published but update in progress to cover points to consider for existing filling lines. Second publication to be in collaboration with Biophorum: BPOG.


2.Environmental Classification, Qualification, Monitoring of GMP controlled areas. Connects all three stages.


3.Localized Uni-Directional Airflow: L-UDAF definition and alignment with ISO UDAF definitions and Annex 1 Grade A air supply definition: includes case study examples.


4.Barrier Leak rates and Leak integrity applied to Pharmaceutical Isolators at Filling line scale.


5.Continuous particle monitoring: Compliance and event monitoring with trend predictor. Facilitates Aseptic process filling from start of monitoring before a one cubic metre compliance sample volume is reached. Trending facilitates incidence rates analysis as KPI.


6.Risk assessment in setting EM sample locations in Isolator filling lines at design stage to facilitate sample system technical integration. Aligns with BPOG EM risk assessment guidance for full cleanroom/ facilities.


7.Airflow visualisation in controlled areas: CFD: Computational Fluid Dynamics (DQ) Smoke studies visualisation of airflow patterns (OQ) and LR Method contamination transfer challenge study (PQ).


8.Moist heat sterilisation key points to consider including avoiding Wet loads in porous load sterilisation.


9.Glove Management strategy for Barrier systems: Isolators and RABS Gloves based on Life cycle approach: Selection, Visual and physical integrity testing, Risk assessment for post batch production leak integrity test failure with consideration of impact.


10.VHP/vH202 bio-decontamination of loads:

A) Loads in: Isolators and Material transfers

B) Bio-compatibility of H202 residuals, impact on biological products and associated impact studies.


11.Definitions of ‘Open and Closed’ applied to aseptic processing.


12.NTT: No-touch-transfer of pre-sterilised ready to use (RTU) product containers into Grade A filling environments following GMP and QRM principles. Guidance covers requirements for pre-sterilised container suitability for NTT (Container supplier and supply chain qualification) and qualification of application in a filling line that applies NTT for Sterile product Aseptic process filling.


13.Contamination Control Strategy: CCS. Annex 1 compliance requirements. Guidance on preparation of a CCS based on three steps: Definition of application and principle contamination control measures for the facility and process by design. Identification of contamination vectors applied to the process/ facility design with associated risk and contamination control strategy based on technical and procedural control measures for each vector of transient and intrinsic contamination.


14.Aseptic-Containment strategy: ACS for processing sterile toxic and biologically hazardous products. Aseptic containment also applies where cross contamination control is required and prepared with an alignment to the CCS. A three step approach is considered: Define hazards based on Health based exposure limits, Set control measures based on two levels of containment; Primary and Secondary containment, Qualification of containment with challenge testing commensurate with level of hazard; Toxic or Bio-Hazard.


15.Media fill – Process simulation design in Aseptic processing. Points to consider for different product and process types with different process durations; batch and campaign.


16.Cleanroom garments selection, gowning qualification, Change-rooms for gowning and behaviour after entering cleanroom. Includes examples of MHRA regulatory observations on Cleanroom behaviour.


17.Disinfectant Rotation: Required? Why, what, when? Considers spectrum of efficacy, material compatibility and justification for rotation or no rotation, as required.


18.PUPSIT and Fluid pathway leak integrity and Sterilising filter configurations in filling lines.


19.Visual inspection of sterile products in final containers and alignment of acceptance criteria between stopper manufacturers and pharmaceutical manufacturers.


20.Definitions of Hold times: Aseptic holds, sample hold, sterile hold, stability holds.

Planning is now finalised for 2020 Aseptic processing workshop syndicates and Annual Challenges in Sterile product manufacturing conference in Manchester UK April and June respectively. These are typically sold out events so those interested should contact the PHSS as soon as information is released. Details of events and content will be released early 2020 to facilitate reservation of places.

The Annex 1 revision status. There is information that in Q1 of 2020 a targeted consultation will be completed by the EMA/IWG; Inspectors Working Group on the next draft of Annex 1 revision. Following review the final draft is expected to be published Q3/Q4 2020 with a period before implementation (without further changes).


The PHSS have sent a letter to the EMA to register interest as an ‘Interested party’ to facilitate joining the targeted consultation alongside other interested parties; including ISPE and PDA.


The Annual PHSS Conference on challenges in sterile product manufacture, June 2020, will include an update of current status of Annex 1 revision with a PHSS ‘Hot Topic’ Annex 1 conference expected once the final draft is published to start to understand content: GMP requirements, QRM application and regulatory expectations.


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