Last week, in LOGFILE 10/2018 you read the first part of this article that covered key changes to European cleaning validation guidance, including setting limits and identifying worst-case active residue that should be part of the cleaning life cycle program. The second part discusses the various QP responsibilities regarding the new set of requirements for cleaning validation.
The QP needs to rely on the PQS3,4,16,17. A robust PQS should trigger an alert to the manufacturer when GMP guidelines are updated. In response, the manufacturer must assess the gap between the current cleaning validation practices and the new set of requirements. A gap analysis must be performed to assess the impact on the product quality, cross-contamination and cleaning risk assessments. Based on the gap analysis result, an implementation approach under a change control process must be developed to achieve compliance. It is the duty of the QP to ensure that these steps have been performed prior to certifying and releasing a batch3. When it is not the case, a deviation must be initiated and an action plan must be identified to achieve compliance.
The implementation approach must be supported by a cleaning risk assessment which can be used to prioritise the PDE residues evaluation. The cleaning risk assessment, in addition to the other cleaning parameters, must take into consideration data such as minimum therapeutic dosage, minimum lethal dose 50 (L/D50), NOAEL, LOAEL, lowest-observed-effect level, thresholds of toxicological concern, occupational exposure level or occupational exposure band. The QP must have visibility of the cleaning risk assessment and monitor the PDE evaluation progress. Finally, based on the prioritisation results, it is acceptable to justify generating the PDE value over a defined schedule.
The QP must confirm that the API manufacturer follows the current EU Guidelines to GMP and Active Pharmaceutical Ingredients Committee document on cleaning validation13,18. The API manufacturers must calculate the residue MACO based on the PDE value18. The PDE value can vary depending on the route of exposure11. It is the responsibility of the QP to ensure that the API PDE value is calculated based on the final drug route of administration. Otherwise, a correction factor for route-to-route extrapolation should be applied if there are clear differences (e.g. > 40%) in route-specific bioavailability6.
Any activity outsourced to a contract manufacturer (CM) should be appropriately defined19. The CM must be qualified in accordance with Chapter 7 of the EU Guidelines to GMP19. It is the responsibility of the CM QP to ensure that the product certified is compliant with current EU GMP. Depending on the contract agreement, the marketing authorisation holder (MAH) must share the PDE value of the different products with the CM. The CM must calculate the new health-based MACO to confirm that the MACO currently used onsite is the safest one. The surface area limit (SAL) and the swab limit must be based on the shared surface area
SAL = MACO (mg)/shared area surface (cm2) = mg/cm2
However, in the event that a part of the production process is started by the MAH and then finished by the CM, the CM should integrate the MAH shared surface area in order to calculate the SAL. The SAL must be applicable for both, unless a scientific justification supports otherwise. It is the responsibility of the QP, based on reliance on the PQS, to ensure that the correct MACO and SAL are calculated to prevent cross-contamination and risk to the patient. Finally, it is the responsibility of the MAH QP to ensure that the PQS of the CM is working and to inform the MAH QP of changes that may impact the decision to certify a batch.
In case the product is from a third country, the QP certifying and releasing the product for the European market is solely and fully responsible for all the manufacturing taking place in the third country3. Therefore, the QP must be able to guarantee that the manufacturing process follows EU GMPs. In addition, the PQS of the manufacturer in the third country should ensure the QP is informed of a change that may impact the decision of certifying and releasing the product.
One of the best ways for the QP to confirm reliance on the PQS is to conduct an assessment by visiting the operations to observe routine practices against the PQS and procedures in place. An example for deficiencies observed during a 2016 audit by the MHRA was that “The QP did not ensure that he had current knowledge of the company PQS”2. Amongst the top 15 deficiencies observed in the field by the United States Food and Drug Administration from FY13 to FY16 were as follows20.
In addition, the MHRA shares examples of deficiencies observed in the field from April 2011 to April 2012, and during 2013, 2015 and 20161,2,21,22.
It is expected that the QP goes to the manufacturing area and that he or she has sufficient understanding of the manufacturing process to judge compliance. Of course, the audit process is delegated to an experienced team of internal auditors. Finally, the QP must be informed of major to critical deficiencies that may impact his or her reliance on the PQS or assessment of product quality.
Finally, for product non-contact areas (e.g. cleanroom, dust collector, facility environment), the cross-contamination risk assessments must be updated to integrate the toxicity and potency risk of existing or new product. Based on the risk assessment result, the decision to dedicate facility, equipment or re-validate the cleaning and disinfection process must be discussed and justified. The QP must be aware of any changes that may impact the cross-contamination prevention procedures in place or the product quality.
It is the responsibility of the QP to make sure that the PQS in place is capable of alerting about any changes in the regulatory requirements for the manufacturing or the cleaning processes that may impact product quality. Adequate and formal communication processes between departments is one of the key features of a robust PQS. The QP will need to rely on the PQS, but should have on-going assurance that this reliance is well founded3. A best practice to confirm reliance on the PQS is by testing it through field observations of routine practices against procedures in place. Finally, the QP must monitor and have an overview of the critical parameters and documents that confirm the product is safe for the patient, including cross-contamination management and control.
Walid El Azab is a Technical Services Manager for STERIS Life Science and a former QP. He currently provides technical support related to cleaning chemistries, disinfectants and sterility assurance products and their application and validation. His areas of expertise include both upstream and downstream biopharmaceutical operation and validation. Walid earned a Master’s degree in Industrial Pharmaceutical Sciences from the University of Liège, Belgium and is a certified Lean Six Sigma green belt. Walid also gives Industrial Pharmaceutical Sciences Master’s courses at the University of Liège. Finally, Walid is an active member of the PDA, ISPE, ECA, A3P and is Secretary of the Belgium QP Association (UPIP-VAPI).
‘This article, ‘Key Learnings from Serialisation Projects’ is reproduced from a recent issue of gmp review, a quarterly journal researched and edited by an expert team experienced in all aspects of pharmaceutical manufacturing and control.
gmp review provides in-depth analyses of international pharmaceutical manufacturing regulations.
gmp review keeps readers up to date on the latest Directives, Regulations and Guidelines applicable to the pharmaceutical industry from the FDA, EU, CPMP and ICH positions. Each item comes with analysis and comment on its effect on your company. The dry legal jargon is made understandable to you and your colleagues in manufacturing and quality. As such gmp review is the perfect companion to the GMP Compliance Adviser and will help provide further useful commentary on the new regulations.
If you are involved in any aspect of GMP then gmp review will provide much needed information and analysis in a convenient quarterly journal format. gmp review subscribers will also receive gmp-review news a monthly news service to keep you up-to-date on new developments in GMP and associated regulations.
For further information on the GMP Review please click on the following link: