Dr. Brendan Griffin Course Director School of Pharmacy, … · Testing lab 2015 FDA WARNING ......

Dr. Brendan Griffin Course Director MSc in Pharmaceutical Technology & Quality Systems School of Pharmacy, UCC

Overview of recent GMP incidents,

483s and warning letters: what have

we learned?

Overview - The GMP history of 2015!

• Trends in FDA Warning letters from

2015

• Key events from EudraGDMP non-

compliance reports in 2015

• Notable GMP events from 2015

• FDA’s Office of Pharmaceutical

Quality initiative

FDA Warning letters categorised over time

0

10

20

30

40

50

60

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Oral solid API Oral Liquid Topical Miscellaneous Pareterals

Inhalable Repacker Testing lab Veterinary Biologics

2015…the year that was

• FY2015 numbers are similar to the last 5 years;

• Aseptic/Sterile parenterals continue to be the lead category

in FDA’s drug warning letters

• Drug GMP warning letters that are not issued to

compounding pharmacies are issued mostly to sites outside

the US

Trends in 2015 WL

• 27/50 related to US based aseptic compounding pharmacies

• 19/50 – issued to manufacturers outside US

• 15/19 of these were issued related to ‘data integrity’ deficiencies.

• All of the drug manufacturing sites where data integrity deficiencies were identified are located outside the US, primarily in India which received 10 of the 15 (67%) warning letters.

• 2/15 were issued regarding firms in the EU (the Czech Republic and Italy)

Oral solid

API

Topical

Miscellaneous

Pareterals

Testing lab

2015 FDA WARNING LETTERS CATEGORISED BY

PRODUCT CLASS

Data integrity observations

• FDA Warning letter, 09/01/2015

• Our inspection identified laboratory test records that you did not review and evaluate in making batch release decisions. These records contained uninvestigated, out of specification (OOS) data.

• …employees in ..Quality Control (QC) laboratories had frequently conducted unauthorized “trial” HPLC injections prior to additional injections that were used in the reported test results.

• …The data from “trial” injections was not reviewed or evaluated when making the batch release decision

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm431456.htm



Data integrity observations • FDA Warning letters, 30/01/2015

• The inspection of your facility documented multiple incidents of performing "trial" testing of samples, disregarding test results, and reporting only those results from additional tests conducted.

• our inspection found that 2,803 of 44,643 injection results were not processed or reported in the official data folder for dissolution analysis

• Your response ..to explain the rationale for retesting based on “the unknown impurity peak…is not characteristic of the product and was not observed in the analysis of all commercial and exhibit batches.” The fact that you did not observe the peak in commercial and exhibit batches does not justify disregarding the test run or failing to follow up with appropriate corrective actions and preventive actions.

• FDA’s concern pertains to the practice of disregarding failing results, conducting trial injections and retesting products without any investigation.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm432709.htm


• FDA Warning letter, 06/04/2015

• the analyst at your firm altered the file name in the spectrophotometer.. to support the release of two previously manufactured lots.

• Your response is inadequate because …A cursory review of records does not ensure that other personnel did not manipulate or inaccurately report test data.

• Your quality unit failed to detect that your laboratory altered IR raw data and misrepresented the results for approval and release



• FDA Warning letters, 27/05/2015 – did not retain complete raw data from testing performed …

– Specifically, our inspection revealed your firm did not properly maintain a back-up of HPLC chromatograms that form the basis of your product release decisions. Our inspection revealed discrepancies between the printed chromatograms and the operational qualification protocol.

– All laboratory employees shared a common log-in and password to access the system.

– Company stated they were unable to retrieve the original electronic raw data because back-up discs were unreadable….since at least 2013.

– However, without complete, accurate, reliable, or retrievable raw data about the HPLC system’s qualification, you lacked complete assurance that the system was operating as intended


• FDA Warning letters, 31/03/2015

– HPLC software, TotalChrom®, did not have sufficient controls to prevent the deletion or alteration of raw data files.

– the investigator observed ..a folder named “Test,” and that chromatographic methods, sequences, and injection data saved into this folder can be deleted by analysts.

– no audit trail function was enabled for the “Test” folder

– We identified a similar inspectional finding during the 2013 inspection of your XX, manufacturing facility … Explain how your firm will implement global corrective actions and preventive actions concerning computer controls and provide a timeline for implementation.


• FDA Warning letters, 29/01/2016

• the original peak had been integrated inconsistently. Standards and samples had been processed using different integration parameters with no documented reason; there were no controls …to prevent analysts from manipulating integration settings in order to obtain passing results… When our investigator asked you to reprocess the chromatograms using appropriate integration parameters, an out-of-specification (OOS) .. was obtained.

• the date and time of the chromatographic injections appear to have been …backdated.

• During the inspection, our investigators spoke with an analyst who reported that ‘if we find a failure, we set back the date/time setting and re-integrate to achieve passing results



• 16 reports of GMP Non-compliance were posted on EudraGDMP in 2015

• 11/16 (69%) cited deficiencies in data management / data integrity.

– 5/11 sites in question are in China;

– 4/11 sites in India and

– 1/11 each in France and Italy.

• This may be an incomplete listing because the competent authorities are not required to post the summary reports for non-compliant inspection outcomes.

- Data Integrity

• Feb 2016 – French Competent Authority issued at API supplier

EudraGMDP Non compliance reports

• Feb 2016 –Spanish Competent Authority issued at Parenteral manufacturer

EudraGMDP Non compliance reports

• Feb 2016 – French Competent Authority issued at IMP manufacturer

Falsified Heparin manufacture

(…again!)

•

• Feb 2016 – French Competent Authority issued at API supplier

GVK Biosciences Data Integrity Issues

• French medicines agency (ANSM) raised concerns about how data integrity issues at GVK Biosciences, an Indian CRO involved in conducting clinical trials (Jan 2015).

• EMA recommended EU member states suspend the marketing authorizations for products whose approval relied on clinical date from GVK, citing concerns over "systemic" data manipulation alleged by ANSM

• ANSM said it uncovered evidence of data manipulations for electrocardiograms (ECGs) that were performed as part of many of the clinical trials.

• EMA stated this "cast doubt on the integrity of the conduct of the trials … and on the reliability of data generated’’.

• ~700MA’s in total affected (~30 in Ireland).

FDA adds ‘Pan drugs’ to the ‘Import Alert’ list

• Investigator observed specific violations during the inspection, including: – Failure to properly maintain, repair, and keep clean buildings used in the

manufacture of APIs in a manner that prevents contamination where open equipment is used. For example,

– Our investigator observed holes in the walls and roof which allowed pigeons access near production equipment in multiple manufacturing areas.

– Gaps and holes in outside walls for piping and air ducts which allow contaminants to enter the building.

• Failure to properly maintain equipment used in the manufacture of APIs and minimize the risk of contamination, where open equipment is used. For example, – Our investigator observed rust, dirt, lubrication leaks, and exposed insulation

material on and around open drug manufacturing equipment.


Canada recall’s of OTC Ibuprofen oral liquid

• A voluntary recall of 126 batches of Ibuprofen oral liquid

(February 2016)

• Type II recall

• Clumps in the bottle – inconsistent dosing – failed uniformity

of dose

• Identified during stability testing

• Xanthan Gum – suspending agent

• Change in supplier of this excipient

Aseptic Manufacturing observations

• FDA Warning letter 27/01/2015

• A number of negative observations have been listed:

– An employee placed a cup on the floor of an ISO 7 area to collect water. When setting up the filling line of the ISO 5 area, employees used that water to wet the mechanical assembly in the piston drive.

– Machine operators crawled on the floor on their hands and knees under the filling line.

– An operator directed vials to the machine with his hand located directly above.

– When setting up, an employee moved an un-bagged sterilised tool directly from the ISO 7 to the ISO 5 area.

– During unloading in the ISO 7 area, an operator dropped a sterilised lid from a container onto the floor. He then picked it up and placed it back on the container.

– Before performing aseptic filling activities in the filling room during aseptic setup, operators wore goggles on their foreheads and exposed skin.

– Operators opened machines to adjust or remove vials with bare hands.

– Operators carried unprotected sterilised material from an ISO 5 to an ISO 7 area and then to the mobile Laminar Air Flow area.

• 27/50 related to US

based aseptic

compounding

pharmacies

Oral solid

API

Topical

Miscellaneous

Pareterals

Testing lab

2015 FDA WARNING LETTERS CATEGORISED

BY PRODUCT CLASS

Remember the NECC

• New England Compounding Centre meningitis outbreak (September 2012)

• 64 deaths associated with fungal contamination of methylprednisolone injection. >800 individuals affected across 20 US states

• Stimulated huge debate in US regarding the freedom of Pharmacists to ‘Compound’ medicines vs. Requirement for ‘Manufacture’ of medicines.

• Compounding vs Manufacturing

So what has happened since • Dec. 2012 - the NECC filed for bankruptcy.

• Sep. 2014 – Supervising pharmacist was arrested before boarding a

plane, and was charged with one count of mail fraud.

– The FDA affidavit states that the Pharmacist used improper sterilization and

testing techniques, unsafe practices, falsified cleaning logs, and ordered

pharmacy technicians to fraudulently mislabel vials.

• Dec. 2014, 14 NECC executives and technicians, including co-founder

and president, were indicted on a host of federal charges ranging

from racketeering, to fraud to second degree murder.

• The pharmacist and President at NECC were charged with helping

orchestrate a conspiracy that led directly to 25 of the deaths.

New powers for FDA

• 2013 – The "Drug Quality and Security Act," – New Law Strengthening FDA Oversight of Compounding Pharmacies.

– Clarifies the authority of the FDA to regulate specialty compounded (altered) drugs

– Creates a new voluntary program for FDA to regulate entities engaged in batch compounding that elect to register with the FDA;

– new 503B, Pharmacy compounders (i.e. those who prescriptions are not made specifically for one patient ) can become an “outsourcing facility.”

– Outsourcing facilities: • must comply with CGMP requirements;

• will be inspected by FDA according to a risk-based schedule; and

• must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound.

FDA oversight of Pharmacy compounders

• ~350 Warning letters issued to over 300 Compounders since

2013

• FDA issued three new guidances on Pharmacy compounding

(2016)

FDA WL to ‘IV ‘Speciality’ Ltd. 25/01/2016

BIA 10-2474 Clinical trial tragedy in France

• Phase I trial of BIA 10-2474 an inhibitor of fatty acid amide

hydrolase (FAAH), an enzyme that breaks down so-called

endocannabinoids in the brain

• Trial conducted by Biotrial, a CRO, on behalf of the sponsor, Bial.

• 128 healthy volunteers. Each received €1,900.

• 86 people received different escalating single doses from Summer

2015 onwards without observing any serious adverse side effects.

• 6 participants fell ill after receiving repeat higher doses over the

course of several days.

• The first participant to fall ill experienced adverse symptoms on 10

January and died on 17 January

• Biotrial halted the trial on 11 January; the other five affected people

were hospitalized in the days that followed.

• At least one of these patients has since been discharged, and the

health of the remaining patients has improved.

• Of the 84 other subjects who received lower doses of the drug, none

has shown any of the symptoms seen in those hospitalized.

Lessons learned to date from BIA 10-2474

• A patient was given a dose of the drug on 7 January and admitted to hospital on the evening of 10 January. But on the morning of 11 January the company carrying out the trial, administered the same dose to five more participants.

• Three major shortcomings have been identified. – Administration of the drug being tested continued even after the first

volunteer had fallen ill,

– The second error was not to inform these volunteers of what had happened the previous evening, to give them the chance to withdraw their consent.

– The third had been not reporting the incident to the French national medicines safety agency (ANSM) until four days after the first volunteer had been admitted to hospital.

Questions remain

• Why has the drug’s chemical structure not been revealed?

• At least five other compounds targeting FAAH have been

developed with limited success over the past several

years…has all the potential adverse effects from previous

trials been reported in the literature?

• Despite six years of preclinical in vivo pharmacological and

toxicological evaluation (in 4 specieis), could ‘off – target’

effects not have been predicted?

Changes in FDA oversight

of Drug Product Quality

Drivers for Change

• Product recall & defect reporting data demonstrate high occurrences of problems attributed to inherent

defects in product/process design.

• Increased shortages of critical drugs related to the use of outdated equipment, aging facilities, and lack of

effective QMS.

• Increasing numbers of post-approval supplements, in part owing to our current practice of “locking in” an

applicant’s manufacturing process before it is fully optimized.

• Current regulatory review and inspection practices tend to treat all products equally. A disproportionate

amount of regulatory attention is devoted to low-risk products and issues, diverting resources needed for the

assessment of high-risk products.

• The FDA has only limited information about the current state of pharmaceutical quality. The FDA has no formal

means for quality surveillance, except through inspections, and lacks resources to comprehensively review

annual reports and other data (e.g., recalls and Field Alert Reports), which may provide significant amounts of

pharmaceutical quality information. Furthermore, inspection findings have not been a reliable predictor of the

state of quality.

• Inspection is not well-connected to knowledge gained from product review.

Office of Pharmaceutical Quality

Office of Pharmaceutical Quality

Office of Program and Regulatory operations

Office of Policy for Pharmaceutical Quality

Drug Products

Office for Testing and Research

Office of Biotehcnology Products

Office of Surveillance

Office of Process & Facilities

Office of New Drug Products

Office of Lifecycle Drug Products

Spider Catches Manufacturer in Web of Deceit

• multiple incidents of inaccurate batch production records containing erroneous statements, including results that were not derived from analytical testing or from your supplier’s Certificates of Analysis (CoAs).

• What tipped off FDA to these "erroneous" statements?

• records are labeled “ANALYTICAL RESULTS OBTAINED BY USING THE OXYGEN ANALYZER.” However, the FDA investigator observed cobwebs between the portable Oxygen Analyzer and the adjacent wall.

• The general manager stated that your firm does not use the Oxygen Analyzer, which directly contradicts your batch production records.


Questions Dr. Brendan Griffin Course Director MSc in Pharmaceutical Technology & Quality Systems School of Pharmacy, UCC [email protected]

mailto:[email protected]

Dr. Brendan Griffin Course Director School of Pharmacy, … · Testing lab 2015 FDA WARNING ......

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