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mercredi 25 mars 2020

WARNING LETTER DermaPharm A/S MARCS-CMS 596662 — MARCH 10, 2020

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).
Your firm receives raw material, "(b)(4)" as a component for use in production of (b)(4). This raw material is a (b)(4) containing (b)(4), the active ingredient in your finished drug product. Though you receive this raw material with a certificate of analysis from your supplier, you have not performed appropriate incoming analysis of component lots upon receipt, including confirming the identity prior to use in production of your finished drug product. You also relied on your supplier's Certificate of Analysis without establishing the reliability of your component supplier's test analyses at appropriate intervals.

mercredi 18 mars 2020

WARNING LETTER Windlas Healthcare Private Limited MARCS-CMS 595494 — MARCH 10, 2020

1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).
Your firm did not maintain complete and accurate data from all laboratory testing. Without reliable laboratory data, you cannot assure appropriate decisions regarding batch release, product stability, and other drug aspects of quality. For example:
a. On May 19, 2018, the peak detection function was disabled multiple times during the gas chromatography (GC) residual solvent testing of your incoming active pharmaceutical ingredient (API), (b)(4) batch (b)(4). After reviewing the chromatograms, our investigators noted unknown peaks that were not reported or integrated as required per your procedure.
Our investigators requested your firm to reprocess the sample set sequence, which subsequently showed > (b)(4)% total unknown impurity peaks. You used this batch of API to manufacture multiple batches of (b)(4) tablets which were released to the U.S. market.
This was not an isolated incident. Our investigators also noted unknown peaks which were not reported or integrated during the method transfer of related compounds testing for (b)(4) USP API batch (b)(4). Your firm did this study to support the (b)(4) for (b)(4) tablets....
b. On April 16, 2019, you cancelled a test sequence during 18-month related substances testing that included (b)(4) mg tablets batch (b)(4). Your investigation stated the cancellation was due to "oven leak error." The chromatogram for this initial run showed impurities that would yield an out-of-specifications (OOS) result. The initial run was invalidated, and you prepared and tested a new sample solution on April 17, 2019. The retest failed percent relative standard deviation (RSD) and you invalidated this second run too. On April 22, 2019, you prepared a third sample solution and repeated the test. The third sample solution also failed percent RSD and again you invalidated the run. On April 29, 2019, you prepared a fourth sample solution. This test yielded passing data. You reported the final, passing data after multiple testing failures. You did not adequately investigate the failing results as required by your laboratory incidents (LI) procedure. Your firm also did not identify clear root causes for the repeated analytical problems that caused you to invalidate the first three analyses.
2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Your investigations into laboratory incidents (LI) testing results are inadequate. Multiple LI investigations lacked adequate scientific rationale for root cause determination. Without adequate scientific rationale, your firm invalidated the failing OOS results that were included in these LI. You subsequently reported the passing retest results.
For example, during your analytical method verification for residual solvent for (b)(4) API, your firm initiated numerous LI concerning failures of the test's accuracy, method precision, or intermediate precision parameters. The probable root causes of these LI were attributed to contamination and analyst error. We note your retesting plans did not specify retesting by an analyst other than the one who performed the original test. In addition, samples were retested until passing results were achieved. Your CAPA for these LI stated "training on standard operating procedure (SOP) of 'Good laboratory practices of QC laboratory' shall be imparted to concern person [sic]." Your method verification report was approved on May 3, 2018. We note that on May 19, 2018, unknown peaks were observed using this test method which were not identified or integrated as discussed in Charge 1 of this letter.

vendredi 13 mars 2020

Avec l'appui de l'IA, IBM s'attaque à la détection du cancer du sein

Technologie : Le département de recherche d'IBM a mis au point une nouvelle méthode de détection des cancers du sein reposant sur l'usage de l'intelligence artificielle. Une avancée majeure pour la santé publique ?

Avec l'appui de l'IA, IBM s'attaque à la détection du cancer du sein
Une étude récente menée par le département de recherche d'IBM a révélé comment la combinaison d'algorithmes d'apprentissage automatique et d'évaluations de radiologues pouvait améliorer la précision globale des dépistages du cancer du sein. Selon Stefan Harrer, chercheur à IBM, les mammographies, couramment utilisées par les radiologues pour la détection précoce du cancer du sein, reposent souvent sur l'expertise d'un radiologue pour identifier visuellement les signes du cancer, ce qui ne s'avère pas toujours précis.
« Dans l'état actuel de l'interprétation humaine des images de mammographie, deux choses peuvent se produire : un diagnostic erroné en termes d'absence de cancer et aussi un diagnostic de cancer lorsqu'il n'est pas présent », explique le cherche, interrogé par ZDNet. « Ces deux cas sont hautement indésirables : on ne veut jamais manquer un cancer quand il est là, mais aussi si l'on diagnostique un cancer et qu'il n'est pas là, cela crée une pression énorme sur les patients, sur le système de santé, qui pourrait être évitée », relève-t-il...

Covidom : l'application française développée en un temps record pour lutter contre le Coronavirus

Technologie : Une solution de télésuivi à domicile pour les patients porteurs ou suspectés Covid-19 vient d'être lancée par l’AP-HP. Elle est déjà en production dans deux hôpitaux parisiens.

Covidom : l'application française développée en un temps record pour lutter contre le Coronavirus
Cette application de e-santé (en cours de validation sur le Google Play Store et d'ors et déjà disponible sur le store iOS) doit permettre le suivi médical à domicile des patients porteurs ou suspectés Covid-19 qui ne nécessitent pas d’hospitalisation assure l’AP-HP (Assistance Publique - Hôpitaux de Paris).

Elle est destinée à tous ceux qui pensent être infectés par le Covid-19 "sans signe de gravité". L'objectif ? Bénéficier d’un télésuivi à domicile via des questionnaires médicaux "proposés une ou plusieurs fois par jour", et ce en complément de mesures de confinement.

Via cette application, un médecin inclut le patient dans le processus (connexion à la plateforme, inscription du patient en saisissant ses données administratives et les données médicales utiles). Ensuite le patient répond quotidiennement à un questionnaire numérique en ligne depuis son ordinateur ou via l’application disponible sur les principaux stores. En fonction de la réponse au questionnaire, l'application peut envoyer des alertes...

lundi 9 mars 2020

Improving Upstream Predictability

Better understanding and control of cell behavior is yielding benefits, upstream and beyond.
Mar 01, 2020
Volume 33, Issue 3, pg 12-14

In the earliest days of biotech, developers often struggled to sustain conditions that would optimize cell health and product yield. Today, better understanding of cells and how they interact with their environment has enabled improvements in most aspects of upstream processing, from bioreactor design and media development to process control, automation, and modeling.
Some of the most significant gains have been made in cell line expression, advanced sensors, and automation, says Atul Mohindra, R&D director for biomanufacturing at Lonza Pharma and Biotech. “Using automation, process analytical technologies (PAT), and advanced multivariate analysis has enabled the industry to control process performance and product quality more closely than ever before,” he adds.

Building Data Quality in Generates Quality Data Out

Ensuring the quality of data in process monitoring and control systems starts in process development phases.
Mar 01, 2020
Volume 33, Issue 3, pg 18–22, 38

As biopharma manufacturers incorporate more data-driven monitoring and control systems in production processes, the quality of the data, as well as integrating, interpreting, and protecting it, become more important. One solution is to build quality features into these systems during process development.
As a process scales, “there is a need to transfer or integrate process development (PD) data; therefore, building data quality into these activities right from the start is important. Management of data quality always facilitates integration with other systems irrespective of the scientific or business purpose,” observes Chris Andrews, a senior solution consultant with Dassault Systèmes BIOVIA.
“In the case of monitoring data during process development, it is critical,” Andrews says, “to identify and segregate valid data intended for technical transfer and to ensure that data are clean (i.e., have few invalid results or records) as possible. Higher quality data will minimize integration time, improve the ability to quickly interpret those data, and offer assurance of data integrity and provenance.”

How Pairing Data Connectivity And Comprehensive Automation Ease Tech Transfer And Scale-Up

Current state: islands of automation
In the biopharmaceutical industry (biopharma), process data is used in many ways throughout process development (PD) and the different production phases. But the pieces of equipment are often connected only by process; that is, the bioprocess material passing between each of them. Often this connection is discontinuous, meaning that equipment is controlled on an instrument level, which results in islands of automation. This article outlines how connectivity and a comprehensive automation solution can ease technology transfer and scaling from PD to final manufacturing scale. Suitable automation solutions also help maximize both manufacturing efficiency and facility utilization.

mercredi 4 mars 2020

WARNING LETTER KVK-Tech, Inc MARCS-CMS 592387 — FEBRUARY 11, 2020

1. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).
Your firm failed to properly integrate co-eluting peaks during impurity testing of phentermine HCL capsules, which resulted in your analysis failing to detect out-of-specification (OOS) results for at least one lot of drug product.
You self-identified this problem in 2016. In a deviation report, you wrote that analysts were using “(b)(4) methods” and the “reported impurity levels may not reflect the true concentrations found in the drug.” Your firm conducted training on May 24, 2016, reportedly to teach analysts to properly integrate and measure closely co-eluting peaks during impurity analysis of your drugs. Despite this training, in December 2016 your analyst performed (b)(4) integration to calculate the area of the peaks for a stability impurity test for Lot 12456A of phentermine HCL capsules. If the appropriate (b)(4) integration had been performed, the test result for the drug product lot would have exceeded the impurity specification limits. This lot remained on the market until it failed (b)(4) stability impurity testing on June 20, 2017. Your secondary quality review of the December assay also failed to detect the error. Multiple examples of your firm’s failure to properly integrate closely co-eluting peaks were observed during our inspection...
3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).
Data generated from your laboratory testing systems is not adequately protected from deletion or alteration. For example, (b)(4) of your quality assurance employees had administrator access privileges in (b)(4) chromatographic testing software, which is used for HPLC assay and impurity analysis of finished drug products.
Additionally, data files could be modified or overwritten without being captured on audit trails on your stand-alone laboratory equipment, including your (b)(4) spectrophotometer, and Fourier transform infrared spectrophotometer...

WARNING LETTER Chemland Co., Ltd. MARCS-CMS 593158 — FEBRUARY 11, 2020

1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
Your quality unit (QU) lacked adequate responsibilities and authorities to assure reliable operations. For example:
A. You failed to ensure the audit trail feature was enabled on your Inductively Coupled Plasma - Optical Emission Spectrometry (lCP-OES) instrument to track creation, modification, or deletion of data. This instrument was used to obtain assay results for your drug products.
B. You stored your master batch records as unlocked Excel files which were open to alteration, duplication, and deletion by unauthorized personnel.
C. Your analysts used open Excel files for documenting sample preparation information and final calculations. These records were not retained. For example, your personnel admitted during the inspection that records and data, such as volume of test solution, sample weight, and final calculations, are not retained.
Manufacturing data must be retained to support CGMP activities including but not limited to your batch disposition decisions, stability studies, and investigations.

WARNING LETTER Acino Products, LLC MARCS-CMS 589471 — FEBRUARY 10, 2020

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).
When requested, your firm could not provide test results to support the microbiological testing results on your certificate of analysis (COA) for bisacodyl and phenylephrine suppositories, yet your firm signed the COA indicating conforming results for microbiological testing and released the batches. During the inspection, you also could not explain whether samples had been sent to your third-party lab for analysis to support the results on your COA.
Your response stated that, going forward, no COA will be signed without receipt of the actual results, but did not include information about the review and management data to support release of your drug products.
In response to this letter, provide:
• A list of
chemical and microbial test methods and specifications used to analyze each lot of your drug products before a lot disposition decision, including but not limited to impurities testing for clotrimazole topical solution.
• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119570/download.

mercredi 26 février 2020

WARNING LETTER Yibin Lihao Bio-technical Co., Ltd. MARCS-CMS 592503 — FEBRUARY 13, 2020

1. Failure to prepare and use production and control records for each intermediate and API batch.
Your site produces crude heparin for purification into finished API. During a pre-inspectional call on July 10, 2019, your firm stated to FDA that you had not manufactured any materials for months. At the start of the FDA inspection on July 31, 2019, your firm stated to the investigator that you were not manufacturing crude heparin and were only per forming equipment testing.
During a walkthrough of your warehouse, the investigator observed a warehouse employee leaving the warehouse with a fiber drum and inquired about the contents of the drum. Your firm stated that the drum contained (b)(4) bags. However. inspection of the drum revealed two batches of crude heparin manufactured just a few days before the FDA inspection (CU190726, (b)(4), manufacturing date July 26, 2019, and CU 190727, (b)(4), manufacturing date July 27, 2019). When asked about manufacturing and testing records pertaining to these two crude heparin batches, your firm told us that you do not have records for the two crude heparin batches....
2. Failure to establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
During the inspection, the investigator observed your firm did not adequately control critical documentation pertinent to the traceability of crude heparin manufactured at your facility. During the walkthrough on July 31, 2019, our investigator observed numerous records on the floor, desks, and cabinets of the Quality Assurance (QA) Office on the third floor of the office building. Some of these records included batch production records for heparin.
During the inspection, one of your employees stated that these records were generated to support an application for government funding, but the crude heparin batches specified in the records had not actually been manufactured. However, later during the inspection, on August 2, 2019, your firm stated that all the records in the QA Office were in fact associated with genuine crude heparin batches.
Additionally, even though your Crude Heparin Sodium Inventory and Distribution Record indicated your firm manufactured (b)(4) batches of crude heparin (CU190601 to CU190730) from June 1, 2019, to July 30, 2019, your firm was only able to provide complete batch records for two batches, CU190728 and CU190730.
Traceability of crude heparin is a critical part of managing quality. You must ensure that a complete contemporaneous record of each batch of drug manufactured is retained for CGMP purposes. Your system for managing quality is inadequate and calls into question the traceability of all drugs, including crude heparin. manufactured at your facility...
Data Integrity Remediation
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA's guidance document Data lntegrily and Compliance with Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/97005/download.
We strongly recommend that you retain a qualified consultant to assist in your remediation...

WARNING LETTER JHS Svendgaard Hygiene Products Ltd MARCS-CMS 593473 — FEBRUARY 13, 2020

1. Your firm failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(2)).
You lacked adequate testing of the incoming (b)(4) active pharmaceutical ingredient (API) to determine assay and other appropriate quality attributes. Instead, your firm relied on your suppliers' certificates of analyses (COA) without establishing the reliability of the suppliers' analyses through appropriate validation.
You must test each component for conformity with appropriate written specifications for purity, strength, and quality unless and until you have appropriately qualified the suppliers and validated their test results at appropriate intervals...
2. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).
Your firm lacked appropriate validation (or verification, for United States Pharmacopeia (USP) compendial methods) of your analytical test methods used to determine acceptability of your drug product before release for distribution.
Analytical methods must be validated to show they are suitable for their intended use, and equivalent or better than applicable USP compendial methods. Verifying the accuracy, sensitivity, specificity, and reproducibility of your test methods is essential to determine if the drug products you manufacture meet established specification for chemical and microbial attributes...

mardi 25 février 2020

Manufacturing quality systems first defense against hackers says expert

An effective quality management system is a must for biopharmaceutical firms looking to protect their data assets against hackers according to a leading cybersecurity expert.
Increasingly biopharmaceutical manufacturing relies on data.
Ensuring optimal conditions are maintained in bioreactors or that chromatography systems are functioning properly depends on monitoring systems that feed information back to control systems.
Image: iStock/stevanovicigor
Likewise, data is key to how biopharmaceutical products are tracked through packaging and distribution systems to ensure they get to the correct hospital, pharmacy or – in the case of personalized medicine – patient.
But while these systems may make manufacturing more efficient and improve product quality, they are also a potential vulnerability.