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VOLUME: 17 - ISSUE: AUG 2015 |
PHARMA UPTODAY
PHARMA UPTODAY
2
Inside this issue
3 News Uptoday
28 New Guidance
39 Audit Findings
483 Observations
EU Non Compliance Rep...
PHARMA UPTODAY
3
News Uptoday
India Proposes $78 Million Fund to Promote Drug Industry Growth
India’s government has annou...
PHARMA UPTODAY
4
Dr. Reddy’s Issues U.S. Recall of Epilepsy, Hypertension Drugs
Dr. Reddy’s Laboratories is recalling drug...
PHARMA UPTODAY
5
Paper dossiers are no longer required to accompany eCTD formatted submissions, following
the success of t...
PHARMA UPTODAY
6
Another clinical research organisation, Quest Life Sciences of Chennai, is in trouble over
defective tria...
PHARMA UPTODAY
7
WHO "notice of concern" in 2014. Micro Labs officials were not immediately available.
The Indian pharmace...
PHARMA UPTODAY
8
The NSSO had asked the state governments to provide information to arrive at a statistical
design for the...
PHARMA UPTODAY
9
Type: DWPE
Import Alert Name:
"Detention Without Physical Examination of Drugs From Firms Which Have Not ...
PHARMA UPTODAY
10
Plot No. P-1 & P-2, , IT-BT Park Phase II, MIDC, Hinjwadi , Hinjwadi, Pune, Maharashtra
INDIA
55 - - - -...
PHARMA UPTODAY
11
Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices These
products are exclud...
PHARMA UPTODAY
12
Sheffield Crown Court this month ordered Fresenius Kabi to pay a fine of £500,000 ($778,000)
and ordered...
PHARMA UPTODAY
13
―The two companies are very closely linked, and the onus is on them both to produce and
supply products ...
PHARMA UPTODAY
14
Many of the drugs Gallant supplied were misbranded and did not contain proper packaging
inserts or instr...
PHARMA UPTODAY
15
This is mainly issued when serious defects were identified but also if the answer to the Form
483 is cla...
PHARMA UPTODAY
16
Article 111b of Directive 2001/83/EC allows an exemption, though: third countries can request a
review o...
PHARMA UPTODAY
17
The company’s solid-state chemistry and analytical functions across its Italy site will also benefit
fro...
PHARMA UPTODAY
18
Observations:
1. The responsibilities and procedures applicable to the quality control unit are not full...
PHARMA UPTODAY
19
The Indian pharmaceutical market, pegged at over Rs 80,000 crore annually, is highly
fragmented with man...
PHARMA UPTODAY
20
The announcement by the Central Drugs Standard Control Organization — part of a five-year
plan — has bee...
PHARMA UPTODAY
21
Lumigan 0.03%, an ophthalmic solution. But that announcement also came with the disclosure
that an inspe...
PHARMA UPTODAY
22
Sandoz shutters German and Indian production sites
Sandoz has revealed it will close three manufacturing...
PHARMA UPTODAY
23
The new medications are known as PCSK9 inhibitors because they block a substance that
hinders the liver’...
PHARMA UPTODAY
24
anomalies. The new observations come just two years after the US drug regulator lifted an
import ban imp...
PHARMA UPTODAY
25
remain with the manufacturers up to the point of sale, where wholesale dealers will take
ownership of th...
PHARMA UPTODAY
26
European Medicines Agency recommendation for an EU-wide ban on the drugs tested at GVK's
Hyderabad, Indi...
PHARMA UPTODAY
27
Terminology
Apparent Cause: The event or action that immediately results in or precedes
the nonconformit...
PHARMA UPTODAY
28
New Guidance
FDA Releases 43 New Product-Specific BE Guidances
The FDA has published dozens of product-s...
PHARMA UPTODAY
29
Guideline on influenza vaccines – submission and procedural requirements
The need to update the current ...
PHARMA UPTODAY
30
management systems for pharmaceutical manufacturing. This guidance includes an
explanation of how the Ce...
PHARMA UPTODAY
31
EMA to Update Guideline on Risk Management Plans
The European Medicines Agency plans an October release ...
PHARMA UPTODAY
32
and Biological Products" finalised for 24 June 2015 the FDA clarifies its point of view and the
correspo...
PHARMA UPTODAY
33
Draft Guidance on Lubiprostone
Active Ingredient: Lubiprostone
Dosage Form/Route: Capsule/oral
Recommend...
PHARMA UPTODAY
34
Important: the data analysis should be assured either by using appropriately validated
software or indep...
PHARMA UPTODAY
35
This guideline replaces the note for guidance on the manufacture of the finished dosage form
(CPMP/QWP/4...
PHARMA UPTODAY
36
What needs to be reported?
FDA asks for data to be compiled and reported on:
 The number of lots attemp...
PHARMA UPTODAY
37
results divided by the total number of tests performed by the establishment in the same
timeframe.
 Ann...
PHARMA UPTODAY
38
What are the challenges?
Certainly a challenge for both industry and FDA will be how to span the scope o...
PHARMA UPTODAY
39
AUDIT FINDINGS - 483 Observations
Firm Name 483 Observation
J. Strickland and Co. - Nov.
26, 2014
Testin...
PHARMA UPTODAY
40
destroyed and subjected to examination, testing or other
investigation to prove the drug products do mee...
PHARMA UPTODAY
41
Feb. 18, 2015 controls designed to assure that the drug products have the
identity, strength, quality, a...
PHARMA UPTODAY
42
Catalent hit with FDA Form 483 at North Carolina plant
Observations:
1. The responsibilities and procedu...
PHARMA UPTODAY
43
Packaging material seems to be a source of foreign matter, but other than vacuuming trays
before packagi...
PHARMA UPTODAY
44
EU Non-Compliance Report: WUXI JIDA PHARMACEUTICAL CO., LTD, China
Nature of non-compliance : The inspec...
PHARMA UPTODAY
45
f) Personnel behavior (deviations 2-7i(ii)-18-19): during the inspection, the inspectors’ team
received ...
PHARMA UPTODAY
46
Failure to prevent unauthorized access or changes to data, and to provide adequate controls to
prevent o...
PHARMA UPTODAY
47
Regulations of the Month
Subpart B--Organization and Personnel
Sec. 211.25 Personnel qualifications.
(a)...
PHARMA UPTODAY
48
Top Presentations of Pharma Uptoday
· Presentation on data integrity in Pharmaceutical Industry
· Data I...
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Pharma Uptoday - Monthly magazine; Volume 17, Issue Aug 2015

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To recap the previous month's pharma highlights to Pharma Uptoday followers, Monthly magazine Volume 17 has been released with the following content.

News Uptoday
New Guidance
Audit Findings
483 Observations
EU Non Compliance Report
- INTEGRA LIFE SCIENCES CORP, United States

- JINAN JINDA PHARMACEUTICAL CHEMISTRY CO., LTD., China

- WUXI JIDA PHARMACEUTICAL CO., LTD, China
- PARABOLIC DRUGS LIMITED, India

Warning Letters
- Mahendra Chemicals, India

Regulations of the Month
- Sec. 211.25 Personnel qualifications
- Sec. 211.28 Personnel responsibilities

Published in: Healthcare
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Pharma Uptoday - Monthly magazine; Volume 17, Issue Aug 2015

  1. 1. VOLUME: 17 - ISSUE: AUG 2015 | PHARMA UPTODAY
  2. 2. PHARMA UPTODAY 2 Inside this issue 3 News Uptoday 28 New Guidance 39 Audit Findings 483 Observations EU Non Compliance Report - INTEGRA LIFE SCIENCES CORP, United States - JINAN JINDA PHARMACEUTICAL CHEMISTRY CO., LTD., China - WUXI JIDA PHARMACEUTICAL CO., LTD, China - PARABOLIC DRUGS LIMITED, India 45 Warning Letters - Mahendra Chemicals, India 47 Regulations of the Month - Sec. 211.25 Personnel qualifications - Sec. 211.28 Personnel responsibilities
  3. 3. PHARMA UPTODAY 3 News Uptoday India Proposes $78 Million Fund to Promote Drug Industry Growth India’s government has announced plans for a $78 million venture capital fund to offer loans to drug companies that are building or expanding manufacturing facilities. The fund would channel public resources into drug design, discovery and development, according to a new report issued by the Department of Pharmaceuticals. The department may also increase funding support to early-stage entrepreneurs in the form of seed capital or by facilitating funding with other financial institutions, the report says. In addition, the task force is proposing offering drugmakers soft loans or interest subsidies to upgrade manufacturing facilities to meet World Health Organization good manufacturing practices. At best, the proposal is a token of the government’s intention to promote drug manufacturing in India, says D.G. Shah, secretary general of the Indian Pharmaceutical Alliance. The $78 million amount is too small to make any real impact, since a U.S. FDA-approvable finished dosage plant typically costs above $25 million, he says. The task force was created to implement the government’s ―Make in India‖ campaign, which mandates boosting the indigenous drug manufacturing sector in the country. FDA Plans to Receive Five Biosimilar Applications Per Year The FDA says it expects to receive five 351(k) applications from companies seeking to file biosimilar product applications in fiscal 2015. In a notice posted to the Federal Register, the FDA says it expects each company to devote 860 hours per response. In addition, it expects two companies to file applications for proposed interchangeable products supplements and devote another 860 hours per response. The FDA says it is still on track to issue draft guidance on demonstrating biosimilar interchangeability to a reference product later this year. Three other biosimilars draft guidances — covering naming, labeling and statistical approaches to the evaluation of analytical similarity data — also are expected this year. Read the notice at www.fdanews.com/6-15-FDA-351kNotice.pdf
  4. 4. PHARMA UPTODAY 4 Dr. Reddy’s Issues U.S. Recall of Epilepsy, Hypertension Drugs Dr. Reddy’s Laboratories is recalling drugs used to treat seizures and high blood pressure from the U.S. market due to dissolution and potency issues. All of the affected products were manufactured at DRL’s Bachupally, Hyderabad, India, facility, FDA enforcement reports show. Four lots of the epilepsy drug divalproex sodium extended-release tablets were recalled because they exceeded dissolution at the nine-hour time point. The voluntary recall, initiated May 22, affects 7,479 100-count bottles and 2,544 500-count bottles of the 250 mg version, along with one lot of the 100-count 500 mg version of the drug. On May 6, DRL launched a recall of the hypertension drug amlodipine besylate and atorvastatin calcium tablets in the following strengths due to subpotency. Affected were one lot of 5mg/40mg packaged in 30-count and 90-count bottles, two lots of 5mg/10mg packaged in 30- and 90-count bottles, one lot of 10mg/40mg in 90-count bottles and two lots of 10mg/10mg in 30- and 90-count bottles. The lots all have an expiry date of July 2015. Development of a Regulatory Framework for Mandatory Reporting by Healthcare Institutions The Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law) introduces a new power to require certain healthcare institutions to report serious adverse drug reactions and medical device incidents. This requirement is intended to improve the reporting of these types of events and enable the timelier identification and communication of emerging safety issues associated with the use of drugs and medical devices. This power will come into effect when accompanying changes are made to both the Food and Drug Regulationsand the Medical Devices Regulations. The regulatory changes will define the applicable healthcare institutions, the data to be provided, and when it must be provided to Health Canada. Objective To implement a new regulatory framework for a national mandatory reporting program, that provides comprehensive information about these types of adverse events while minimizing the operational impact on healthcare institutions. Prescription medicines: Submissions in the eCTD format now in Australia Prescription medicine sponsors can now submit dossiers to the TGA in the electronic Common Technical Document (eCTD) format.
  5. 5. PHARMA UPTODAY 5 Paper dossiers are no longer required to accompany eCTD formatted submissions, following the success of the pilot programme between January and June 2015. Paper dossiers are also not required to accompany Non-eCTD electronic Submissions (NeeS). Guidance documents are currently being updated to reflect that paper copies are no longer required. Transition period Until 31 December 2015, applicants have the option to use either the version 0.9 or 3.0 specification for their submission.  Submissions in version 3.0 are valid from 1 June 2015 onwards.  Submissions in version 0.9 will be accepted until 31 December 2015.  From 1 January 2016, sponsors must submit their application using version 3.0 if submitting in the eCTD format. About eCTD The Australian eCTD format is a specification for the pharmaceutical industry to submit electronic applications to register medicines on the Australian Register of Therapeutic Goods (ARTG). The eCTD format enables the faster, safer and more consistent exchange of information between the TGA and industry. It allows the TGA to conduct review processes for quality, safety and efficacy electronically. The eCTD format supports the Australian Government's digital transition policy, and will:  deliver significant cost savings to industry, by eliminating the cost of shipping and archiving paper dossiers  cut red tape and it make it easier and more reliable to conduct business  reduce the impact on the environment, and  allow sponsors to reuse electronic dossier information when they submit their application to other regulatory authorities WHO Finds Evidence of Data Manipulation at Indian CRO Quest Life Sciences
  6. 6. PHARMA UPTODAY 6 Another clinical research organisation, Quest Life Sciences of Chennai, is in trouble over defective trials work, according to a warning issued by the World Health Organization. The action by the United Nations health agency follows an earlier scandal over drug testing at GVK Biosciences, which resulted in approvals for hundreds of generic drugs being withdrawn in Europe. India's drug industry, a source of cheap generic medicines to countries worldwide, has been tarnished in recent years by a series of quality problems at various companies, including manufacturing and clinical data shortfalls. In the case of Quest, the World Health Organization (WHO) said there had been "critical" lapses in a trial of HIV drugs, including the fact that two-thirds of patients' electrocardiograms (ECGs) turned out to be duplicates. "Subject details ... and dates had been changed by the company, in the majority of cases, to make the ECGs appear as if they were from each of the different subjects," it said. The WHO inspectors also criticised the standard of record-keeping in the trial, including apparent attempts to hide documents from inspectors. The WHO, which checks on medicines used by UN agencies like UNAIDS and UNICEF, issued a "notice of concern" to Quest last week. Joseph Kamlesh, Quest's head of operations, told Reuters the issue was isolated and could not be compared with the problems at GVK, which concerned multiple regulators. "We expect this issue will be resolved in six months. We have not lost any contracts or clients, we have a very good relationship with them," he said. Quest has around 100 clients that it serves on and off, but for the past two to three years it has been working for 25 companies, he added. Its work has been used to support drug applications in Europe, the United States, Australia, Russia, South Africa and the Philippines, according to its website. Kamlesh said that since the WHO's surprise audit of its facilities last October, it had also been visited by US, British and Spanish regulators. "The FDA ( US Food and Drug Administration) has cleared our plant after making some initial observations, while the Spanish and UK authorities are yet to issue a final response," he said. Quest's trial of HIV drugs was carried for India's Micro Labs, which was itself the subject of a
  7. 7. PHARMA UPTODAY 7 WHO "notice of concern" in 2014. Micro Labs officials were not immediately available. The Indian pharmaceutical contract research market is expected to reach $1 billion in 2016, from $485 million in 2012, according to consultants Frost & Sullivan. But some executives fear it could be undermined by reputational issues. Health ministry initiates sampling on spurious, NSQ drugs at 12 notified ports Following completion of sampling of spurious and not-of-standard quality (NSQ) drugs as a part of a nationwide survey on spurious and NSQ drugs, the Central Drugs Standard Control Organisation (CDSCO) in association with National Institute of Biologicals (NIB) has initiated collection of all formulations and APIs imported into the country through 12 notified ports. The survey is being done in collaboration with Indian Statistical Institute (ISI) and National Sample Survey Organisation (NSSO). It is a pan-India project in which drug samples were drawn from healthcare institutions and retail pharmacies across the country to assess the quality of drugs available to the common man. This will be followed by testing and analysis of the samples and drafting of the final report. As a part of the survey, samples have been collected from 665 of the total 676 districts of the country based on a statistical design. Collection of 43000 samples have been done successfully encompassing all the retail drug stores including government medical stores, CHCs and PHCs as part of the pan-India survey. Around 36,000 samples have already been sent for testing at drug testing labs across the country. There are 6 central drug testing labs, 3 state drug testing labs at Maharashtra, Vadodara and Karnataka. An official associated with the development explained that around 1000 drug inspectors from across the country were trained for the pan-India initiative. Dr Surinder Singh, director, National Institute of Biologicals (NIB), Noida, is the chairman of the committee conducting the survey. This broad-based survey would help in identifying the geographical areas where spurious drugs are available so that a focused monitoring is done by the concerned authorities in these areas for eliminating the menace of spurious drugs. Earlier, a survey to assess the extent of spurious drugs in the country was conducted in the year 2009 by the ministry of health, which revealed that the extent of drugs found spurious was 0.046 per cent only.
  8. 8. PHARMA UPTODAY 8 The NSSO had asked the state governments to provide information to arrive at a statistical design for the survey like information such as the number of retail outlets (district-wise); information regarding the maximum prescription of drugs under each of the 15 categories including their trade name district wise; number of civil hospital stores (district-wise); number of central medical store (state-wise); and number of Central Government Health Scheme (CGHS) dispensaries throughout the country. The CDSCO formulated the survey plan in consultation with NIB for conducting a scientific study on the extent of problems of spurious drugs and drugs not of standard quality (NSQ). Through this initiative between the state and the centre, India will now be able to project a clear statistics on spurious drugs, thus clarifying India’s stand on the same with scientific evidence. US FDA bans imports manufactured at Emcure’s Indian plant India’s Emcure Pharmaceuticals has been banned from shipping any of the drugs manufactured at its Maharashtra-based facility to the US, according to an import alert from the US FDA. The FDA doesn’t go into detail about the GMP (good manufacturing practice) violations cited in the import alert but it does say the alert includes antibiotics made at the facility. Emcure has seven other Indian manufacturing facilities, mostly producing generic drugs and APIs (active pharmaceutical ingredients), and one manufacturing facility in New Jersey that makes soft-gelatin capsules. Products manufactured at the Indian site listed on the import alert are distributed in the US by New Jersey-based Heritage Pharmaceuticals. Lew Soars, VP of marketing at Heritage, told us the company was ―caught by surprise‖ with the import alert and is ―still trying to assess it.‖ Back in February, Heritage announced a voluntary US-wide recall of 10 lots of Colistimethate for injection and three lots of Rifampin manufactured by Emcure due to ―FDA observations pertaining to aseptic and GMP practices at the manufacturer's site potentially impacting product sterility.‖ That same month, Sagent Pharmaceuticals recalled two lots of a muscle relaxant and pulled manufacturing back in-house after product sterility was called into question by the FDA. In May 2014, another recall of Teva products came as that site’s lab testing was not followed in accordance with GMP requirements Import Alert # 66-40 Published Date: 07/13/2015
  9. 9. PHARMA UPTODAY 9 Type: DWPE Import Alert Name: "Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs" Reason for Alert: *** Foreign inspections of pharmaceutical manufacturers are being performed. Detention without physical examination may be appropriate when an FDA inspection has revealed that a firm is not operating in conformity with current good manufacturing practices (GMP's). Detention without physical examination may also be appropriate when FDA receives information concerning inspections conducted by foreign or other government authorities under a Memorandum of Understanding or other agreement that FDA concludes reveals conditions or practices warranting detention of either particular products or all products manufactured by a firm. DWPE of such firms remains in effect until such time as FDA is satisfied that the appearance of a violation has been removed, either by reinspection or submission of appropriate documentation to the responsible FDA Center. *** Guidance: *** Districts may detain, without physical sampling and analysis, the indicated drug products from the foreign processors noted in the Red List of this import alert. Foreign processors listed on the Red List of this import alert who would like to request removal from that list should provide information to FDA to adequately demonstrate that the manufacturer has resolved the conditions that gave rise to the appearance of the violation, so that the agency will have confidence that future entries will be in compliance. This may include a letter detailing its corrective actions, accompanied by documentation. For guidance on removal from detention without physical examination, refer to FDA-s Regulatory Procedures Manual, Chapter 9, "Detention Without Physical Examination (DWPE)." Information supporting removal should be sent to CDER's Office of Compliance, (HFD-300). *** Emcure Pharmaceuticals Limited Date Published : 07/13/2015
  10. 10. PHARMA UPTODAY 10 Plot No. P-1 & P-2, , IT-BT Park Phase II, MIDC, Hinjwadi , Hinjwadi, Pune, Maharashtra INDIA 55 - - - -- Pharm Necess & Ctnr For Drug/Bio Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices 56 - - - -- Antibiotics (Human/Animal) Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices These products are excluded from dwpe: Amikacin inj, antibiotic / 56D[][]06 60 - - - -- Human and Animal Drugs Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices 61 - - - -- Human and Animal Drugs Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices These products are excluded from dwpe: Ondansetron inj. Antiemetic (for nausea/vomiting)/61T[][]26 Prochlorperazine inj, Antiemetic (for nausea/vomiting)/ 61T[][]14 Metoclopramide inj, used for GERD and antiemetic / 61T[][]12 62 - - - -- Human and Animal Drugs Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices These products are excluded from dwpe: Zoledronic Acid inj, treats/prevents osteoporosis / 62A[][]05 Cidofovir inj, treats eye infection in HIV patients / 62V[][]21 Carmustine inj, cancer / 62I[][]12 Efavirenz / 62V[][]24 63 - - - -- Human and Animal Drugs Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices 64 - - - -- Human and Animal Drugs Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices 65 - - - -- Human and Animal Drugs Date Published: 07/13/2015 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices 66 - - - -- Human and Animal Drugs Date Published: 07/13/2015
  11. 11. PHARMA UPTODAY 11 Notes:All Drugs All Antibiotics Problem(s): (GMP) Good Manufacturing Practices These products are excluded from dwpe: Haloperidol inj, Antipsychotic / 66M[][]98 Sandoz closing Mumbai API plant but says it remains committed to India Sandoz will shutter an Indian API facility in 2016 as part of a manufacturing refocus in the region. The Turbhe site in Mumbai is one of three Indian manufacturing facilities owned by Sandoz but in a statement sent to this publication, the firm said the facility will close by the end of 2016. According to the generics-focused Novartis subsidiary, Sandoz is refocusing its manufacturing setup in India as part of a general strategy to optimize its global manufacturing network. The site employs around 170 workers and makes active pharmaceutical ingredients (APIs) and antibiotics from its two facilities. One facility produces cephalosporin products while the other makes the API for β-lactam compound carbapenam API, as well as and sterile injectables. “We made the announcement today to ensure our associates are informed as soon as possible about our decisions and to ensure a transparent process,” said Sandoz Country Head in India, Vivek Devaraj. “We are committed to managing the process with the utmost care, sensitivity and respect for all impacted associates at Turbhe, to supporting our customers through the transition and to meeting patient needs for access to important medicines.” Despite the announced closure, Sandoz says it remains committed to India and the Indian market through its other two sites – the Mahad API facility and the Kalwe oral solid dosage, both located in the Maharashtra State – which produce over three billion tablets and 180 tonnes of API annually, as well as employing over 1,300 people. Fresenius Kabi fined £500,000 after patient death Fresenius Kabi and a UK drug manufacturer have been sentenced for supplying faulty insulin syringes which contributed to a diabetic man’s death. British man Neil Judge died at the Northern General Hospital in Sheffield, England in 2010 after being treated with pre-filled syringes that turned out not to contain insulin. He suffered a serious episode of diabetic ketoacidosis which triggered multi-organ failure. The defective syringes were supplied to the hospital by Fresenius Kabi as a licensed wholesaler for manufacturer Calea UK Ltd.
  12. 12. PHARMA UPTODAY 12 Sheffield Crown Court this month ordered Fresenius Kabi to pay a fine of £500,000 ($778,000) and ordered to pay a further £5,900 ($9,100) in costs after pleading guilty to breaching the UK Medicines Act. Calea UK was fined £50,000 with £5,900 costs after also pleading guilty to similar breaches. Second syringe failure A coroner ruled the failure of the medicine – which resulted in Mr Judge being deprived of insulin for 13 hours – was a ―major contributory factor‖ in his death. The court was told this was not an isolated incident and that Calea had manufactured and supplied to another faulty batch of pre-filled Tobramycin syringes to a hospital in 2011. The syringes were administered to a patient with cystic fibrosis, but found to contain three times their labelled dose after the patient reported a fizzing sensation. There were no lasting adverse effects. During the prosecution by the Medicines and Healthcare products Regulatory Agency, the court heard the incidents followed inspections by the MHRA of Fresenius Kabi and Calea’s shared site in Runcorn, UK. The visits highlighted concerns about reporting protocols for product defects. Reaction Alastair Jeffrey, Head of Enforcement at MHRA, commented on the sentencing: ―Fresenius Kabi Ltd and Calea UK Ltd are equally responsible for the medicinal failure that was a major contributing factor in the tragic death of Neil Judge, who was deprived of the vital insulin his body needed because of a serious manufacturing error. ―Thankfully the patient who was administered an overdose of tobramycin was relatively unharmed, but the consequences could have been more serious had hospital staff not responded to his complaints.
  13. 13. PHARMA UPTODAY 13 ―The two companies are very closely linked, and the onus is on them both to produce and supply products that are fit for purpose and that conform to precise specifications for each and every batch.” A spokesperson for Fresenius Kabi told us the company expresses its condolences to Mr Judge’s family and that ―the issue [was] fixed immediately after the incident occurred‖ in 2010. The error only affected products supplied to the UK, he added. Life ban for founder of fake US drug company with $12m in sales The founder of a phony pharma company which made $12m importing fake chemo drugs to the US has been banned for life by the US FDA from working with any pharma businesses. The US regulator issued Talib Khan, co-founder of sham medicines company Gallant, with an order banning him permanently from providing services to anyone with an approved or pending drug application. The ban follows Khan’s 2014 conviction of two felonies: one for introducing misbranded drugs into interstate commerce, and the other for criminal conspiracy. The Federal Drug & Cosmetic Act requires the FDA to debar anyone convicted of a felony related to regulation of a drug under the Act. Gallant Pharma International Inc, which Khan co-founded and co-owned between 2009 and 2013, was ―a company dedicated to the illegal importation and sale of misbranded and non- FDA approved chemotherapy drugs and injectable cosmetic drugs and devices in the US,‖ said the FDA. Criminal conspiracy Khan directed international drug suppliers to ship chemotherapy drugs and injectable cosmetic drugs and devices to the UK and Canada, and then arranged for the goods to be sent on to the US. But Gallant Pharma was not licensed as a wholesaler of prescription drugs by the state of Virginia, where it operated. Additionally, some of the drugs and devices Khan sold were not approved by the FDA for use in the US.
  14. 14. PHARMA UPTODAY 14 Many of the drugs Gallant supplied were misbranded and did not contain proper packaging inserts or instructions in English. They also lacked FDA-required labelling to track the production and sale of drug batches. FDA Inspection Reports: What is What Repeatedly we receive questions with regard to the various inspection reports of the U.S. Food and Drug Administration (FDA). Following we will introduce the three main documents: Form 483 This form with the eponymous number 483 is used by the executing Inspector (FDA Investigator) to document the deficiencies he found. It is issued at the end of the inspection and should be answered officially. This response is expected within 15 working days after its issuance. Only then it is guaranteed that the statement will be taken into account in a possible Warning Letter (see below). Sometime, in the case of reasonable compliance, no 483 is issued. EIR: Establishment Investigation Report The EIR is also created by the Inspector in addition to the form 483. This should be done within 30 working days. The EIR is then examined by the responsible Center or District Office of the FDA, issuing the following statuses:  NAI: No Action Indicated - there were no objectionable items found during the inspection  VAI: Voluntary Action Indicated - objectionable items were found, but no action is required on the part of the authority. All of the company's actions are on a voluntary basis.  OAI: Official Action Indicated - objectionable items were found and further regulatory measures will be derived (e.g. Warning Letter). The EIR is forwarded to the inspected company. As part of the so-called 'Freedom of Information Act' it can also be requested by other companies, though. But experience has shown that the disclosure of a foreign EIR may take some time. Warning Letter
  15. 15. PHARMA UPTODAY 15 This is mainly issued when serious defects were identified but also if the answer to the Form 483 is classified as inadequate. It is released - after a review by the responsible Center/ District Offices, not the Inspector himself. The company must respond within 15 working days and explain in detail how to resolve the deficiencies on the one hand and how a recurrence can be prevented on the other hand. Warning Letters are generally published on the homepage of the FDA. In the aftermath, other unpleasant consequences for the company may apply:  Influence on the approval The authorisation for one or more products will not be granted. Applications will not be processed.  Import Stop / FDA Import Alert The company's product (or products) may no longer be imported into the United States. The goods remain at customs.  Debarment List This list comprises all persons who are not allowed to produce pharmaceutical products for the American market. TheDebarment List is freely available.  Court - Consent Decree For American companies and its subsidiaries it can be obtained legally that for several months to years a consulting company will check the company and streamline systems and processes. A final inspection is carried out at the end. In the meantime, profits can be skimmed off. Written Confirmation: Now also Israel and Brazil on the "Third Countries List" Since 2 July 2013, each API delivery from a non-EU country to the EU must be accompanied by a GMP compliance certificate ("Written Confirmation"). With this certificate the authority of the exporting country confirms that it has a control system to comply with GMP standards that is equivalent to the control system binding in the EU and that the exported batches of the API were manufactured according to these standards.
  16. 16. PHARMA UPTODAY 16 Article 111b of Directive 2001/83/EC allows an exemption, though: third countries can request a review of their systems for the monitoring and enforcement of GMP standards with the European Commission. If the review is positive the country is added on a "third countries list". This "third countries list" is part of an EU Commission Decision that is updated when further countries are added to the list. This decision usually becomes effective on the twentieth day following its publication in the official journal of the European Union. The inclusion of Israel and Brazil in this list took place a few days ago with the release of the "COMMISSION IMPLEMENTING DECISION (EU) 2015 / 1057 of 1 July 2015 amending Implementing Decision 2012/715/EC of establishing a list of third countries with a regulatory framework applicable to active substances for medicinal products for human use and the included control and enforcement activities ensuring a level of protection of public health equivalent to that in the Union". More third countries - such as New Zealand and South Korea - have also asked for the exemption and are currently being reviewed, so that it can be expected that the list will be further extended in the near future. Aptuit expands to bring on later-stage capabilities following client demand CDMO (contract development and manufacturing organization) Aptuit is investing in additional scale and capabilities at its Italian site to augment its 1600L scale API capability and to add a commercial GMP license. The expansions are centered on formulation development, analytics and clinical manufacturing to serve Phase III clients and those looking toward commercialization. The company’s integrated CMC (chemistry, manufacturing and controls) solutions, which are currently used by many of the top 20 pharma companies, will now be able to produce commercial APIs as well as capsules and tablets at batch sizes in the range of millions, which should be sufficient for Phase III and commercial purposes. Aptuit is also adding lab scale nanomilling, hot melt extrusion, and spray drying capacity equipment including SEDDS/SMEDDS (Self-microemulsifying drug delivery system) technology.
  17. 17. PHARMA UPTODAY 17 The company’s solid-state chemistry and analytical functions across its Italy site will also benefit from XRPD (X-Ray Powder Diffraction), new surface area equipment and Z Potential/Dynamic Light Scattering as well as two new HPLC (high performance liquid chromatography) systems. Johnathan Goldman, CEO of Aptuit, explained to Outsourcing-Pharma.com that the company is seeing a shift in industry where clients are beginning to prefer ―this under-one-roof solution, rather than having to get API and drug product from multiple places‖ and companies. ―We didn’t choose to go into this market, it came to us via existing customers,‖ Goldman said, noting that customer demand was the driver of the expansions, which also added an unspecified number of new employees to the Italian facility. Catalent hit with FDA Form 483 at North Carolina plant Following an FDA inspection in March, Catalent’s Center of Excellence for Analytical Services in Morrisville, NC was hit with a Form 483 with six observations. The FDA found that not only didn’t the company follow its responsibilities and procedures applicable to the quality control unit, the company’s laboratory controls also ―do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.‖ The inspectors also found that the site -- which is home to Catalent's inhalation franchise including product development, clinical and commercial manufacturing – failed to thoroughly review unexplained discrepancies of whether or not batches had already been distributed. In addition, written production and process control procedures were found to be ―not followed in the execution of production and process control functions.‖ Deviations from written production and process control procedures were also not justified, according to the inspectors. More specifically, FDA inspectors noted that during the review of multiple deviation reports, ―it was observed that stability testing was performed outside the stability testing date range as prescribed,‖ and Catalant also ―failed to mention a non-proceduralized practice that tracks stability sample due dates using an informal Excel spreadsheet as a potential root cause of the deviations.‖ Catalent spokesman Chris Halling told us: "I can confirm that on March 20, 2015, following a routine inspection of Catalent’s Morrisville, NC facility, the US FDA made six 483 observations. Catalent responded by immediately effecting measures to resolve the observations. The FDA later recommended approval of the Morrisville facility for the manufacturing and testing of the products concerned."
  18. 18. PHARMA UPTODAY 18 Observations: 1. The responsibilities and procedures applicable to the quality control unit are not fully followed. 2. laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. 3. There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. 4. Written production and process control procedures are not followed in the execution of production and process control functions. 5. Procedures describing the warehousing of drug products are not followed. 6. Deviations from written production and process control procedures are not justified. DCGI's mobile drug testing labs to check fake medicines Grappling with sale of fakemedicines in the country, the government has now decided to strengthen its regulatory mechanism. The health ministry will soon start mobile drug testing laboratories for surprise checks of medicines available in the market. The drug regulator, drugs controller general of India (DCGI), is working with various institutions including Indian Institute of Technology as well as international regulatory agencies like the US Food and Drug Administration (US FDA) and China's FDA to understand the feasibility of the project. "We have discussed the proposal with the ministry. We are currently talking to various international regulators to understand the mechanism as it works in these countries. We are also talking to institutes here to get technology," DCGI GN Singh said. While the project has already been implemented in Gujarat and has received good reviews, the Central government now plans to roll out such mobile laboratories across the country. However, it will be done in phases, Singh said. In the first phase, the regulator is targeting to launch the programme in three states — Uttar Pradesh, J&K and Himachal Pradesh — by the end of this year. According to Singh, mobile drug testing laboratories will carry equipment for primary testing of samples. The idea is to do surprise inspections, while also saving on resources.
  19. 19. PHARMA UPTODAY 19 The Indian pharmaceutical market, pegged at over Rs 80,000 crore annually, is highly fragmented with many companies and even more number of products. This makes it difficult for regulatory agencies to keep track of products that are sold in the market, mainly in rural areas. Though regulatory agencies collect samples for testing at regular intervals, the massive size of these samples takes a lot of time and resources. According to the regulator, use of mobile testing laboratories will enable drug inspectors to segregate fake and counterfeit medicines at the factory and chemist itself and only those samples which are suspected to be lacking in quality will be brought for further verification. Recently, CBI director Anil Sinha said fake drugs market in India is taking shape of transnational organised crime which may adversely affect the economy. U.S. FDA Adding Staff at India, China Offices The U.S. Food and Drug Administration expects to boost its China office staff to 35 within the next two years and its India staff to 23 as the agency focuses on increasing inspections in both countries. The agency’s China office currently boasts 12 Americans and two local staffers, said Leigh Verbois, incoming director of the China office. Growing the office has been hampered by a Chinese visa process that could take up to two years, but that has recently been cut to just weeks, she told a session at the DIA annual meeting June 16 in Washington, D.C. Meanwhile, the FDA’s India office is set to grow from 12 agency and four local staffers to 19 Americans and four locals, said Matthew Thomas, acting country director. The FDA’s offices in India and China conduct preannounced and unannounced inspections, but are focusing on the preannounced visits to build confidence with local drugmakers and educate them about FDA regulations. Earlier this year, Indian officials accused FDA investigators of conducting unannounced inspections of drug manufacturers without Indian inspectors present (IPRM, February). The FDA denied the allegations, saying it was working on plans to incorporate Indian investigators into the inspection process. CDSCO Hiring 147 Inspectors to Beef Up GMP Compliance India’s national drugs authority will hire 147 inspectors this year to ensure adherence to good manufacturing practices, but training will determine success, an observer says. The new hires will inspect pharmaceutical facilities for their manufacturing processes, drug testing, storage methods and staff qualifications. They will also investigate cases of counterfeit or sub-quality drugs.
  20. 20. PHARMA UPTODAY 20 The announcement by the Central Drugs Standard Control Organization — part of a five-year plan — has been anticipated, says Vince Suneja, CEO of TwoFour Insight Group. The plan, which runs through 2020, calls for creating 1,195 new posts, including 64 experts, although no more specific information is given. In fiscal 2014-2015, CDSCO used roughly 58 percent of its allocated funds while many job vacancies went unfilled, according to a parliamentary report. The key will be whether the vacancies will be filled by competent personnel, Suneja tells IPRM. Training will depend upon programs offered by CDSCO, with support from the U.S. Food and Drug Administration’s India office. The promise to hire a new set of inspectors should mean that India will be able more rapidly and effectively to police India-based pharmaceutical manufacturing, which will only benefit the more responsible drug manufacturers in India and the public, says Mark Barnes, a partner at law firm Ropes & Gray. The FDA recently found multiple manufacturing process violations in a few India-based manufacturing plants, and this new initiative by CDSCO likely represents one governmental response to those citations, he tells IPRM. Lupin gets first U.S. manufacturing base with buyout of GAVIS India's Lupin has landed its first manufacturing site in the U.S. with an $880 million deal to buy a small generics maker in New Jersey that specializes in niche products including dermatology controlled substances. The all-cash deal is for GAVIS Pharmaceutical which was founded by Veerappan Subramanian and has been producing products since 2009. It has a 45,000-square-foot manufacturing and R&D operation in Somerset, NJ and 124,000 square feet of packaging and distribution operations. The company has another 105,000 square feet of newly constructed manufacturing space coming online by the end of 2015. Lupin will be taking on GAVIS' 250 employees. "This is a pivotal acquisition for Lupin as it aligns with our goal to expand and deepen our US presence," Lupin CEO Vinita Gupta said in statement. Lupin has said it wants to release 15 to 20 new products in the U.S. this year, and this deal will go a ways toward doing that. Together, the companies will have 101 products in the market and another 164 pending approval, as well as a pipeline of more to come. GAVIS, which had $96 million in sales last year, has 66 ANDA filings pending approval with the FDA and another 65 in development. Lupin said that 72% of the filing are of niche dosage forms. While Lupin is shooting to expand its U.S. drug production, it has stumbled some on the manufacturing side. Lupin in February said its plant in Pithampur that makes contraceptives and eye drugs for the U.S. had gotten FDA approval to produce a generic version of Allergan's
  21. 21. PHARMA UPTODAY 21 Lumigan 0.03%, an ophthalmic solution. But that announcement also came with the disclosure that an inspection of the plant had resulted in 6 observations. Last year it had to recall 10,000 bottles of its Suprax antibiotic in the U.S. The pills fell short of standards for purity. Capsugel expanding Encap plant on rising HPAPI demand Capsugel is doubling the size of a facility in Scotland to support demand for the encapsulating of drugs containing high-potency active pharmaceutical ingredients (HPAPIs). The Edinburgh, UK facility was taken over by Capsugel when the dosage form solutions firm bought Encap Drug Delivery in March 2013 . The plant is one of the largest in the world to manufacture liquid and semi-solid filled capsules but is now set to double in size through the addition of 40,000 sq ft of production space. Stephen Brown, Managing Director of Capsugel’s Encap Drug Delivery division, told this publication the expansion was due to rising customer demand for its encapsulating services―across the entire pharma spectrum,‖ and across global markets. ―We are seeing demand both at development scale – which is growing at around 40% per year – and for commercial products,‖ he said, adding that two products encapsulated at the site were approved last year with a further NDA submitted so far in 2015. High potency demand But one specific driver for the deal is the rise in high-potency active pharmaceutical ingredients (HPAPIs) among drugmakers, and the demand for services to support this. Encap has been offering such services since 2008, Brown said, but this expansion will double the facility's capacity for HPAPI encapsulation. The expansion is likely to lead to new jobs at the site, though Brown did not divulge how many. However, he told us the workforce has increased by over 50% since the Capsugel acquisition, with the headcount presently standing at 110. He also said the Encap business is now ―completely integrated within Capsugel’s DFS (Dosage Form Solutions) unit and works very closely with its other facilities around the world.‖ The news is the latest expansion for Capsugel, which last month completed a $25m spray-dried dispersion (SDD) plant at a site in Bend, Oregon, and in March announced it was investing the same amount to expand production of its vegetarian food and drug capsules across sites in South Carolina, Mexico, France and Japan.
  22. 22. PHARMA UPTODAY 22 Sandoz shutters German and Indian production sites Sandoz has revealed it will close three manufacturing sites in Germany and India. Head of Sandoz Richard Francis told investors this week he made the ―difficult decision‖ to improve cost efficiency of manufacturing in the ―very competitive‖ generics sector. The sites in Gerlingen and Frankfurt, Germany and Turbhe, near Mumbai, India will close by the end of 2016. Antibiotics and oral The Gerlingen facility manufactures generic oral solids, including ibuprofen, cetirizine, amlodipine and omeprazole. Frankfurt makes cephalosporin antibiotics, (7-ACA) while Turbhe is an API site for Sandoz’s antibiotics business. German manufacturing will remain in Europe, with Gerlingen’s production transferred to Sandoz’s Strykow site in Poland and Barleben in Germany. Cephalosporin will move to Sandoz’s giant antibiotics facility in Austria. Turbhe will send its manufacturing to the company’s other Indian sites. A Sandoz spokesperson told us several hundred jobs will be cut during the moves, ―however we are keeping a strong presence in Germany – and India, with jobs also being created elsewhere.‖ Sandoz had a successful Q2, as parent company Novartis revealed this week the generics business saw core operating income of $423m for the quarter, a 30% increase on 2014. In April, the company received FDA approval for Glatopa, the first generic of Teva’s Copaxone for MS. A court ruled this week Sandoz may launch Zarxio in September, a biosimilar of Amgen’s Neupogen. New cholesterol-lowering medications likely to trigger fight over prices The Food and Drug Administration this week is expected to approve the first in a new class of cholesterol-lowering medications that could represent the most significant advance in cardiology since statin drugs hit the market decades ago. But, in part because the new treatments have yet to demonstrate that they reduce the incidence of strokes and heart attacks, their approval appears set to trigger the latest fight over the high price of many drugs in the United States. Experts have estimated that the new medications could cost $7,000 to $12,000 a year. That’s far less than expensive specialty drugs for cystic fibrosis, certain cancers andhepatitis C, but it is far more expensive than many existing statin drugs, which now come in cheap generic forms.
  23. 23. PHARMA UPTODAY 23 The new medications are known as PCSK9 inhibitors because they block a substance that hinders the liver’s ability to remove bad, or LDL, cholesterol from the blood. [New cholesterol-lower drugs likely to bring new fight over drug prices] Should the FDA approve the new medications, it probably would do so for only some patients initially — for instance, those who can’t get their cholesterol levels low enough with statins or those with an inherited disorder that can severely elevate LDL levels. But some health-care providers and insurers already are fretting about the collective cost of the drugs should they eventually be used to treat millions of Americans with elevated cholesterol levels. ―This sets up an epic battle between insurers and physicians and patients,‖ said Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, who is involved in studies testing two of the new treatments under development. ―It’s an interesting dilemma.‖ Nissen said he thinks the FDA would be justified in approving the drugs, even for limited populations, because they have shown a remarkable ability to reduce bad cholesterol levels in clinical trials and are likely to help reduce cardiovascular events over the long term. That said, he acknowledged that such a scenario could create conflict between doctors who might want to prescribe the drugs for a broader swath of patients and payers who might not be willing to approve such ―off label‖ uses without more data. Aurobindo Pharma comes under USFDA lens, again Hyderabad-based Aurobindo Pharma is the latest addition to an expanding list of Indian drug firms that have come under the scanner of the US health regulator. During a recent week-long inspection at its Unit 12 manufacturing site, the Food and Drug Administration raised issues related to the quality management systems of the company, a person with direct knowledge of the scrutiny said. The inspection that concluded last week had found shortcomings in the facility management procedures of the site besides issues with handling of investigation processes. "However, the company has taken up the task of addressing the issues and will file the remediation report with the FDA," this person said on the condition of anonymity as he is not authorised to speak on the subject. Aurobindo's Unit 12 is used mainly to export the US products like tazobactam and piperacilin, an anti-bacterial injection. An email sent to the investor relations representative of the company on Monday for details on the inspection went unanswered. An Aurobindo Pharma spokesperson declined to comment when contacted over the phone. Though no disruption of supply is expected in the short term because of the observations, the FDA is said to have directed the company to furnish detailed plans for correction of the
  24. 24. PHARMA UPTODAY 24 anomalies. The new observations come just two years after the US drug regulator lifted an import ban imposed on one of Aurobindo's important manufacturing facilities, named in the industry circles as Unit 6. The FDA had also inspected the Unit 6 facility recently and found that the company had addressed the issues which were "minor" in nature, a source said. In the last couple of years, Indian generic drug makers have come under intense scrutiny of the US FDA for non-compliance of good manufacturing practices. Since 2013, the FDA has issued import ban on 22 Indian drug makers, mainly owing to deviations in their manufacturing practices. The US remains an important market for leading Indian generic makers, contributing as much as half their export revenue. For Aurobindo, it is no different. For the quarter ended March 31, 2015, the company reported a net profit of Rs 403 crore on net sales of Rs 3,142 crore, over 50% of which came from US exports. Issues related to manufacturing quality of drugs have dogged the global drug industry alike, cutting across innovators as well as generic makers. A June 2015, a report by Boston Consulting Group focusing on the quality of manufacturing in the biopharma industry and its possible solutions, noted that from 2010 through 2014, 11 of the top 15 biopharmaceutical companies received warning letters from the US FDA. It further added that the manufacturing quality levels in the drug industry remained well below those in other industries, such as semiconductor manufacturing and aerospace. "Such problems can come at a steep price - in some cases hundreds of millions of dollars in lost revenue, remediation costs that can run in the tens of millions of dollars, and a big hit to the company's reputation," BCG said in its report. European Supply Chain: A Series of New Regulations in Force The new EU Directive 2011/62/EU and its delegated acts keep on changing the pharmaceutical supply chain. The directive introduced numerous Delegated Acts with different time schedules and had some impact on revisions of several chapters of the EU-GMP Guidelines. Here is the status quo of the Directive and the delegated acts: Already in 2011, the European Commission published Directive 2011/62/EC, the so-called Falsified Medicines Directive (or FMD).The main goal was the fight against counterfeit medicines. In 2014 the technical characteristics of one key requirement were defined, the unique identifier delivering the possibility of verification of the authenticity of single folding boxes. This will be a 2D barcode (data matrix). As this new requirement will become active in 2018, it is time to start defining strategies for both technical implementation and change control strategy. The new GDP Guidelines apply not only to the wholesalers and manufacturers of pharmaceuticals; they also incorporate the specific requirements for the Brokers dealing with pharmaceutical products. The responsibility for the product during storage and distribution will
  25. 25. PHARMA UPTODAY 25 remain with the manufacturers up to the point of sale, where wholesale dealers will take ownership of the products. It is clear that those playing a role in the pharmaceutical supply chain now have to comply with these requirements. Therefore, the service providers such as transportation companies and logistic service providers need to gain good understanding of what is required to be able to provide appropriate service to their clients. In 2014, the Pharmaceutical Inspection Co-operation Scheme PIC/S published a PIC/S Guide to Good Distribution Practice for Medicinal Products (PE 011-1). This Guide is based on the EU GDP-Guidelines (2013/C 343/01) and quotes the EU Guide almost completely. However, EU-specific references have been deleted and the term "must" is often replaced by the term "should." A dedicated Responsible Person is not introduced by the PIC/S document. It talks about "designated responsible person(s)" or "designated person(s)." Chapter 2.2 "Responsible person" of the EU GDP Guide is not quoted in the PIC/S document. Fallout from India's GVK means $1B lost in drug exports by March 2016 The fallout from a European Union-wide ban on more than 700 drugs that were bioequivalency- tested by India's GVK BioSciences could cost India at least $1 billion in exports by the end of the fiscal year in March 2016, the Economic Timesreports. The "majority of those 700 generic drugs are either produced or sourced by the domestic and multinational pharmaceutical companies in India," the director general of India's Pharmaceuticals Export Promotion Council (Pharmexcil), P.V. Appaji, said to reporters in the southern city of Hyderabad, according to the Economic Times. "We estimate that the loss of exports could be $1-1.2 billion this fiscal." He added that India exported $15.2 billion of pharmaceutical products in the year ended March 31, 2015, with the European Union accounting for a fifth of that figure, or $3 billion. Germany's Federal Institute for Medicines and Medical Products posted the notice of the ban in German on July 22, Business Standard reported. The notice showed the acceptance of a
  26. 26. PHARMA UPTODAY 26 European Medicines Agency recommendation for an EU-wide ban on the drugs tested at GVK's Hyderabad, India, facility. The ban will come into effect on Aug. 21 in a move that New Delhi had tried to head off with diplomatic efforts, the failure of which has apparently riled India's Commerce Ministry the Economic Times said. "The commerce ministry is not happy with the latest development of the European Commission going ahead with ban even after series of consultations we had with the respective European agencies," a commerce ministry official told the Economic Times. "We are reviewing the situation and will decide shortly on the course of action." Appaji separately told the newspaper that among the steps ahead are consultative discussions with stakeholders and a possible complaint to unspecific multilateral forums. In another article, the Economic Times said GVK BioSciences may sell its clinical trials business. Citing people familiar with the development, the newspaper said talks to sell the business, which it said accounts for 10% of the revenues of GVK BioSciences, are underway. GVK CEO Manni Kantipudi
  27. 27. PHARMA UPTODAY 27 Terminology Apparent Cause: The event or action that immediately results in or precedes the nonconformity. May also be called Obvious Cause, Direct Cause, Immediate Cause Root Cause(s): The original event(s), action(s), and/or condition(s) generating (directly or in cascade) an actual or potential undesirable condition, situation, nonconformity or failure. Contributing Causes: Contributing causes are causes that taken alone would not cause the problem but can increase the risk of the issue to happen. Analysis for these causes generally require taking small steps (or a finer look) to be identified and fixed. Root Cause Analysis (RCA): The process of identifying all the causes(root causes and contributing causes) that have or may have generated an undesirable condition, situation, nonconformity or failure. Containment -the action to mitigate impact of the problem and protect the operations/customers (stop the problem getting worse). Includes correction, immediate corrective action, immediate communication and verification that problem does not degrade Root cause (or Permanent) corrective action effectiveness: Actions taken to verify that the planned actions have permanently prevented recurrence of the identified root cause(s).
  28. 28. PHARMA UPTODAY 28 New Guidance FDA Releases 43 New Product-Specific BE Guidances The FDA has published dozens of product-specific draft guidance documents offering recommendations on the design of bioequivalence studies to support ANDAs. The documents cover 43 drug products, including some that are still protected from generic competition — among them, Sovaldi (sofosbuvir) and Olysio (simeprevir) for hepatitis C, Jardiance (empagliflozin) for type 2 diabetes, Northera (droxidopa) for hypotension and Xtandi (enzalutamide) for metastatic prostate cancer. Sofosbuvir also is an active ingredient, along with ledipasvir, in the hepatitis C drug Harvoni. Both drugs are made by Gilead Sciences and have come under intense criticism for their cost. The list also includes such long-time treatments as aspirin and nitroglycerin. In addition to the new guidance documents, the FDA issued revised drafts for three therapies: antibiotic Doryx (doxycycline hyclate), platelet inhibitor Effient (prasugrel hydrochloride) and anticonvulsive Gabitril (tiagabine hydrochloride). The agency issues product-specific BE recommendations periodically. Read the notice on the new and revised drafts here: www.fdanews.com/6-15-FDA-BE- Notice.pdf. The individual guidances are at www.fdanews.com/6-15-FDA-BE-Guidances.pdf. The Drug Supply Chain Security Act Implementation: Product Tracing Requirements for Dispensers-Compliance Policy; Guidance for Industry, Availability The Food and Drug Administration (FDA or we) is announcing the availability of a guidance for industry entitled ―DSCSA Implementation: Product Tracing Requirements for Dispensers— Compliance Policy.‖ This guidance announces FDA's intention with regard to enforcement of certain product tracing requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act) added by the Drug Supply Chain Security Act (DSCSA). FDA does not intend to take action against dispensers who, prior to November 1, 2015, accept ownership of product without receiving product tracing information, prior to or at the time of a transaction or do not capture and maintain the product tracing information, as required by the FD&C Act. Source: https://www.federalregister.gov/articles/2015/07/06/2015-16401/the-drug-supply-chain- security-act-implementation-product-tracing-requirements-for
  29. 29. PHARMA UPTODAY 29 Guideline on influenza vaccines – submission and procedural requirements The need to update the current guidelines regarding the development of influenza vaccines was recognised in the wake of the 2009-2010 influenza pandemic, as the Agency conducted its ―lessons learned‖ exercise. Since then, experience has also been gained through the evaluation of scientific advice and marketing authorisation applications for influenza vaccines. As announced in the Concept paper,1 the revision of the guidelines on influenza vaccines has been organised with the aim of developing a consolidated influenza guideline that covers the regulatory, quality, non-clinical and clinical aspects of influenza vaccine development and dossier submission. The present module compiles with the regulatory and procedural requirements for the different types of influenza vaccines, in line with the scope described under section 2. Source: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_ guideline/2015/07/WC500189035.pdf FDA publishes Analytical Procedures and Methods Validation for Drugs and Biologics Guidance for Industry: This guidance supersedes the draft of the same name that published on February 19, 2014 (79 FR 9467) and replaces the 2000 draft guidance for industry on Analytical Procedures and Methods Validation and the 1987 Guidelines for Submitting Samples and Analytical Data for Methods Validation. It provides recommendations on how you, the applicant, can submit analytical procedures and methods validation data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. It will help you assemble information and present data to support your analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and supplements to these applications. The principles in this guidance also apply to drug substances and drug products covered in Type II drug master files (DMFs). Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM386366.pdf FDA Publishes "Request for Quality Metrics Guidance for Industry": Quality metrics are used throughout the pharmaceutical industry to monitor quality control systems and processes and drive continuous improvement efforts in drug manufacturing. These metrics can also be used by FDA: to help develop compliance and inspection policies and practices, such as risk-based inspection scheduling of drug manufacturers; to improve the Agency’s ability to predict, and therefore, possibly mitigate, future drug shortages; and to encourage the pharmaceutical industry to implement state-of-the-art, innovative quality
  30. 30. PHARMA UPTODAY 30 management systems for pharmaceutical manufacturing. This guidance includes an explanation of how the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) intend to collect data and use quality metrics to help ensure that their policies and practices continue to support continuous improvement and innovation in the pharmaceutical manufacturing industry. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM455957.pdf An Addendum to ICH M7 provides practical Examples to calculate compound-specific Acceptable Intakes The ICH M7 Guideline has reached Step 4 of the ICH process in June last year. It outlines recommendations for the assessment and control of mutagenic impurities that are present or expected to be present in drug substances or drug products, taking into consideration the intended conditions of human use. In Section 7.2.1 of the Guideline it is stated that "Compound-specific risk assessments to derive acceptable intakes should be applied instead of the TTC-based (Threshold of Toxicological Concern-based) acceptable intakes where sufficient carcinogenicity data exist." These compound-specific acceptable intakes (AIs) can be calculated for known mutagenic carcinogens by linear extrapolation based on their carcinogenic potency. In the recently published Addendum to ICH M7 entitled "Application of the principles of the ICH M7 Guideline to calculation of compound-specific acceptable intakes" the statement of the M7 Guideline is picked up. AIs and PDEs (PDE = permitted daily exposure) of 15 compounds are calculated. These compounds were selected because they are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M7. Every calculation is supported by a rationale for selection of study for the AI or PDE calculation followed by a comprehensive list of publications about the toxicological studies of the respective compound. The Addendum to M7 was published on 10 July 2015. It has reached Step 2 of the ICH process and is currently open for comment. An audio and slide presentation from 2 FDA representatives (Aisar Atrakchi and Stephen Miller; ICH topic lead and deputy topic lead for ICH M7) is also available on the ICH website.
  31. 31. PHARMA UPTODAY 31 EMA to Update Guideline on Risk Management Plans The European Medicines Agency plans an October release of its revised GMP guideline and template for risk management plans. The updated Module V — one of 16 chapters in a broader pharmacovigilance guideline — will define ―risk management plan‖ and align risk definitions with the International Conference on Harmonisation. The risk definitions will provide clarity on what is important and what is not, Eli Lilly’s Valerie Simmons told a session at the DIA annual meeting in Washington, D.C. The guideline’s focus is on evidence-based risk identification, Simmons said. RMPs should be driven by data, not procedure type, taking into account the seriousness of events, their frequency and the patient and benefit/risk impacts to establish an association between certain events and the drug. RMP submissions are required only with the initial marketing authorization application and when safety specifications, pharmacovigilance or risk-management activities change. Marketing authorization holders should consider updating their RMPs after submitting new data to the EMA. When creating an RMP, companies should use available data and plan for the future by considering the drug product’s life cycle. A wide net should be cast to capture potential safety concerns at the approval stage, Simmons said. New information about major risks or missing information should be added once scientific evidence confirms it and preferably at key stages in the authorization process, such as the first renewal at five years postauthorization or the first periodic safety update report following renewal. Simmons pointed out that an important potential risk can become an important identified risk after data confirms it. Likewise, an important potential risk can be removed if data fails to confirm concerns. The guideline also provides guidance on postauthorization safety studies, noting that only those required or requested by the EMA’s Pharmacovigilance Risk Assessment Committee or Committee for Medicinal Products for Human Use should be included in the risk-management plan. New FDA Guidance for Industry on the Allowable Excess Volume in Injectable Drug Products Usually, there is a slight overfilling in small volume injectable drug products, especially for biological active ingredients, in order to guarantee the excess volume. In its actual FDA Guidance for Industry "Allowable Excess Volume and Labelled Vial Fill Size in Injectable Drug
  32. 32. PHARMA UPTODAY 32 and Biological Products" finalised for 24 June 2015 the FDA clarifies its point of view and the corresponding requirements. The guidance for industry only refers to drugs in ampules or vials that are intended for injection. Other packaging types (such as prefilled syringes and intravenous infusion bags) or noninjectable products are not mentioned. Background: Injectable vial misuse, including unsafe handling and injection techniques, has led to more cases of vial contamination - especially in multiple-dose containers - and with that to an increased risk of bloodborne illness transmission between patients. According to the FDA inappropriate excess volume and labelled vial fill sizes are two factors that may contribute to this misuse. With its recommendations in this guidance the FDA intends to prevent an overfilling of vials without sufficient reasons. The details of the final guidance for industry "Allowable Excess Volume and Labelled Vial Fill Size in Injectable Drug and Biological Products" were already commented in the news "New FDA Guidance to Avoid Overfill in Vials" on the draft of the document on 31 March 2014. Gastroparesis: Clinical Evaluation of Drugs for Treatment Guidance for Industry The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment of diabetic and idiopathic gastroparesis. Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding clinical trial designs and clinical endpoint assessments to support development of gastroparesis drugs. Gastroparesis is a disorder of the stomach characterized by delayed gastric emptying (DGE) in the absence of mechanical obstruction; symptoms are chronic with episodic symptom exacerbation (Parkman, Hasler, et al. 2004). It predominantly affects young adult females, and the burden of this disease on the individual (morbidity and mortality) and society (health care costs) is considerable (Jung, Cheung, et al. 2009). Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM455645.pdf
  33. 33. PHARMA UPTODAY 33 Draft Guidance on Lubiprostone Active Ingredient: Lubiprostone Dosage Form/Route: Capsule/oral Recommended Studies Two options: for Q1 and Q2 products, and for non-Q1 and -Q2 products Source:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM224220.pdf FDA Guidance on analytical procedures and methods validation published The Guidance for Industry entitled "Analytical Procedures and Methods Validation for Drugs and Biologics" was published by FDA on 27 July 2015. It replaces the draft document which appeared in February 2014. Apart from editorial amendmends the current guidance differs from the previous version mainly with respect to the following aspects:  A risk based approach on the need for revalidation of existing analytical methods is encouraged when changes in the manufacturing process occur during the product's lifecycle. Likewise applicants are required to periodically evaluate the appropriateness of a product's analytical methods in case of new information e.g. regarding the product CQAs or the impurity profile. New or alternative analytical methods based on risk assessments should then be considered.  Appropriate statistical methods should be selected among the variety of statistical techniques and appropriate literature should be consulted for information on statistical procedures when - developing new test methods - evaluating existing test methods - evaluating measurement system performance - interpreting or treating of analytical data like determining equivalence of two test methods.
  34. 34. PHARMA UPTODAY 34 Important: the data analysis should be assured either by using appropriately validated software or independent verification for correctness. Moreover chapter X. "References" has been updated by including revised gudelines, newly edited articles and three ASTM Standard Guides. New EMA Guideline on the Manufacture of the finished Dosage Form Although the title draft Guideline on Manufacture of the finished Dosage Form might indicate that the content of this new guideline relates to manufacturing of investigational medicinal products and/ or marketed products, it does not introduce new GMP requirements. The guideline applies to the description of the manufacturing method in the application, namely in the CTD Module 3 of the marketing authorisation dossier. This guideline should be read in conjunction with Directive 2001/83/EC Article 8.3 (d) (ref 2) where it is stated that the application for a marketing authorisation shall contain a description of the manufacturing method. The requirements on the description of the manufacturing method are described in Annex 1of the directive and are further elaborated in this new guideline. The guideline replaces the Note for Guidance on the Manufacture of the finished Dosage Form (CPMP/QWP/486/95) with the aim to:  reflect changes to the format and content of the Common Technical Document (CTD) Module 3 dossier  address current manufacturing practices in terms of complex supply chains and worldwide manufacture  take into account principles of the ICH Q8 guideline and - as a result - provide clarification on the type and level of information that should be included in the CTD Module 3 of the marketing authorisation application (MAA) dossier with respect to the manufacturing process description. The headings of the guideline follow the structure of the CTD format Module 3, Section 3.2.P.3 Manufacture. Only product specific aspects of manufacture need to be described and included in the MA-dossier; general elements of Good Manufacturing Practice (GMP) should not be included. EMA draft Guideline on manufacture of the finished dosage form
  35. 35. PHARMA UPTODAY 35 This guideline replaces the note for guidance on the manufacture of the finished dosage form (CPMP/QWP/486/95). The note for guidance has been updated to reflect changes to the format and content of the Common Technical Document (CTD) Module 3 dossier. It also addresses current manufacturing practices in terms of complex supply chains and worldwide manufacture. In addition, the content and principles of the ICH Q8 guideline (ref 1) is also taken into account. This guideline does not introduce new requirements on authorised medicinal products for human use. However as stated in article 23 of Directive 2001/83/EC (ref 2) after an authorisation has been issued, the authorisation holder must, in respect of the methods of manufacture and control take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods. Source: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/07/ WC500189407.pdf FDA publishes Quality Metrics Guidance In the last months, the U.S. Food and Drug Administration (FDA) has set up an initiative to use Quality Metrics for planning their risk based inspections. This development was triggered by the Food and Drug Administration Safety and Innovation Act (FDASIA; Title VII, section 706). The goal of the Guidance is to give FDA the authority to collect Quality Metrics from production sites supplying APIs, medicinal products, Biotech, OTC etc. to the US. They should provide data about the "quality level" in each manufacturing site. By this, FDA wants be able to see how well quality systems are maintained. In the future companies will need to conduct continual monitoring, assessment and reporting on the state of quality across their drug products and facilities regulated by FDA. This should then enable FDA to schedule inspections based on risk assessment, improve the efficiency and effectiveness of these inspections and also reduce product-related shortages and recalls. FDA also wants to "encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing".
  36. 36. PHARMA UPTODAY 36 What needs to be reported? FDA asks for data to be compiled and reported on:  The number of lots attempted of the product.  The number of specification-related rejected lots of the product (during or after manufacturing).  The number of attempted lots pending disposition for more than 30 days.  The number of OOS results for the product, including stability testing.  The number of lot release and stability tests conducted for the product.  The number of OOS results for lot release and stability tests for the product which are invalidated due to lab error.  The number of product quality complaints received for the product.  The number of lots attempted which are released for distribution or for the next stage of manufacturing the product.  If the associated APRs or PQRs were completed within 30 days of annual due date for the product.  The number of APRs or PQRs required for the product. FDA intends to calculate the following Quality Metrics for each product and establishment (where applicable):  Lot Acceptance Rate = 1 - x (x = the number of specification-related rejected lots in a timeframe divided by the number of lots attempted by the same establishment in the same timeframe).  Product Quality Complaint Rate = the number of product quality complaints received for the product divided by the total number of lots of the product released in the same timeframe.  Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished product invalidated by the establishment divided by the total number of OOS test
  37. 37. PHARMA UPTODAY 37 results divided by the total number of tests performed by the establishment in the same timeframe.  Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number of APRs or PQRs completed within 30 days of annual due date at the establishment divided by the number of products produced at the establishment. Who needs to report? FDA intends to request the submission of data from establishments that are required to register under section 510 of the Food, Drug and Cosmetic (FD&C) Act and that are subject to inspection under section 704 of the FD&C Act (704 allows inspections of regulated entities). Establishments that receive requests under section 704(a)(4) would be encouraged to submit quality metrics data also for certain foreign establishments that are not required to register. So basically the Guidance applies to every legal entity engaged in the manufacture, preparation, propagation, compounding, or processing of a drug product for the US market or an API used in the manufacture of such a drug product. FDA sees the Quality Control Unit (QCU) generally to be the one to compile the reports. How many reports should be submitted? FDA intends to get one report for each finished dosage form and one report for each API of a covered drug product. When do the reports should be submitted? Reports should be submitted after request. Quality metrics data reports should be submitted for a one-year period that begins after FDA issues its requests. They should then be submitted within 60 days of the end date of the reporting period. What will happen in the case of non-reporting? This will change FDA's risk assessment and may lead to an earlier inspection. In addition, the respective products may be deemed adulterated and subject to enforcement action.
  38. 38. PHARMA UPTODAY 38 What are the challenges? Certainly a challenge for both industry and FDA will be how to span the scope of all segments like branded, generic, biotech and OTC products, APIs, various finished dosage forms (solid oral, modified release, liquid, sterile, etc. and domestic and foreign products with possible language barriers. This will create a lot of data. And Quality Metrics are just one part of the picture, intended to be enhancing FDA's analysis but not replacing existing measures. The program will likely need to learn and evolve through continuous improvement. Comments and suggestions regarding the Draft Guidance for Industry "Request for Quality Metrics" should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. EMA Pre-Authorisation Procedural Advice for Users of the Centralised Procedure This guideline considers issues associated with the processing of renewals in the centralised procedure, with an aim of giving procedural guidance to marketing authorisation holders (MAHs). It has been developed by the CHMP following consultation of the interested parties and the European Commission Services. This guideline is not legally binding, and in case of doubt, reference should be made to the appropriate EU Directives and Regulations. Source: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_ guideline/2015/07/WC500190636.pdf
  39. 39. PHARMA UPTODAY 39 AUDIT FINDINGS - 483 Observations Firm Name 483 Observation J. Strickland and Co. - Nov. 26, 2014 Testing and release of drug product for distribution do not include appropriate determination of satisfactory conformance to the final specifications prior to release. Galena BioPharma, Inc. - Nov. 21, 2014 There is no quality unit. Carlsbad Technology, Inc. - Nov. 21, 2014 Returned drug products held, stored or shipped before or during their return under conditions which cast doubt on their safety, identity, strength, quality or purity are not destroyed and subjected to examination, testing or other investigation to prove the drug products do meet all the necessary parameters. Bachem Americas, Inc. - Nov. 7, 2014 The Quality Control Unit failed to ensure that deviations are fully investigated and/or resolved to prevent reoccurrence. Chemica, Inc. - March 12, 2015 Stability indicating systems have not been developed and validated. Kobo Products, Inc. - March 13, 2015 The Quality Unit is not an independent unit and does not have the responsibility to review and approve quality related documents such as but not limited to production batch records, complaint investigations, and standard operating procedures. Fallon Wellness Phamacy, LLC - March 10, 2015 Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions. Independent Nutrition Centers, Inc. - May 15, 2015 You did not hold cleaning compounds, sanitizing agents, pesticides, pesticide chemicals or other toxic materials in a manner that protects against contamination of components, dietary supplements or contact surfaces. J. Strickland and Co. - Nov. 26, 2014 Testing and release of drug product for distribution do not include appropriate determination of satisfactory conformance to the final specifications prior to release. Galena BioPharma, Inc. - Nov. 21, 2014 There is no quality unit. Carlsbad Technology, Inc. - Nov. 21, 2014 Returned drug products held, stored or shipped before or during their return under conditions which cast doubt on their safety, identity, strength, quality or purity are not
  40. 40. PHARMA UPTODAY 40 destroyed and subjected to examination, testing or other investigation to prove the drug products do meet all the necessary parameters. Bachem Americas, Inc. - Nov. 7, 2014 The Quality Control Unit failed to ensure that deviations are fully investigated and/or resolved to prevent reoccurrence. Pfizer Pharmaceuticals Ltd. - April 17, 2015 Laboratory control procedures are not followed. McNeil Consumer Pharmaceutical Products - March 27, 2015 Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Brown's Compounding Center, Inc. - April 27, 2015 There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Lupin Ltd. - April 3, 2015 Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that components and drug products conform to appropriate standards of identify, strength, quality and purity. Amgen Technology Ireland - April 2, 2015 There is a failure to conduct comprehensive reviews of the changes and additional software codes functionalities made to the Drug Product Filling Line and the revalidation of these software codes as necessary based on these reviews to assure that the ** filling line performs according to its CGMP software applications to prevent filling line non- conformance reoccurrences and to ensure that other software functionalities were not affected as the results of these additions. Genzyme - March 18, 2015 The quality unit failed to establish adequate controls to prevent the introduction of microorganisms during the production of sargramostim BDS as evidenced by non-host contamination events. Monosol Rx, LLC - April 3, 2015 Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. Paragon BioTeck, Inc. - April 3, 2015 The responsibilities and procedures applicable to the quality control unit are not in writing. Triad Isotopes - April 16, 2015 You did not follow written quality assurance procedures. B&P Industrial, Inc. - April 1, 2015 There is no quality control unit. Newton Laboratories, Inc. - There are no written procedures for production and process
  41. 41. PHARMA UPTODAY 41 Feb. 18, 2015 controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Health Plus, Inc. - Feb. 17, 2015 The laboratory control processes that you established and followed were not reviewed and approved by quality control personnel. Custom Compounding Center - April 9, 2015 Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include validation of the sterilization process. Sheffield Pharmaceuticals, LLC - March 19, 2015 Not all of the actions needed to correct and prevent the reccurrence of nonconforming product and other quality problems have been identified. Ferndale Laboratories, Inc. - April 24, 2015 There is a failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. PolyCarbon Industries, Inc. dba PCI Synthesis - April 23, 2015 Your firm failed to assure reworked product was thoroughly investigated and conforms to appropriate standards. Petnet Solution, Inc. - April 13, 2015 You did not follow procedures to ensure that each batch of a PET drug product was given final release before an appropriate laboratory determination was completed. Altaire Pharmaceuticals, Inc. - April 13, 2015 The responsibilities and procedures applicable to the quality control unit are not fully followed. Episciences, Inc. - April 10, 2015 Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Brookfield Medical/Surgical Supply, Inc. - April 9, 2015 There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. Avrio Biopharmaceuticals, LLC - April 3, 2015 Aseptic processing areas are deficient regarding air supply that is filtered. Fenwal International, Inc. - March 25, 2015 Reserve drug product samples are not retained and stored under conditions consistent with product labeling. Warner Chilcott Company, LLC - March 6, 2015 The responsibilities and procedures applicable to the quality control unit are not fully followed. Baxter Healthcare S.A. dba Baxter Healthcare of Puerto Rico - Feb. 6, 2015 The responsibilities and procedures applicable to the quality control unit are not fully followed.
  42. 42. PHARMA UPTODAY 42 Catalent hit with FDA Form 483 at North Carolina plant Observations: 1. The responsibilities and procedures applicable to the quality control unit are not fully followed. 2. laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. 3. There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. 4. Written production and process control procedures are not followed in the execution of production and process control functions. 5. Procedures describing the warehousing of drug products are not followed. 6. Deviations from written production and process control procedures are not justified. EU Non-Compliance Report EU Non-Compliance Report: INTEGRA LIFE SCIENCES CORP, United States: Nature of non-compliance : 1. Contamination of Absorbable Collagen Sponges with particulate matter is not under control. ACS sheets are exposed to an ISO Class 7 environment without protection by Grade A air. This is relevant during the loading and unloading of the cross-linking chamber, the cutting of the sponges, the visual inspections and the (re)packaging stage. Embedded particles do occur but are not always removed during visual inspection if seen. During visual inspection tweezers are used constantly to remove visible contaminants from the surface of sponges. This is regarded by the company as a part of routine production. A comprehensive analysis of the root cause of contamination is not conducted.
  43. 43. PHARMA UPTODAY 43 Packaging material seems to be a source of foreign matter, but other than vacuuming trays before packaging (which proved to be insufficient) no preventive measures have been taken. Static charges contribute to the problem of particulate matter contamination, as was seen by a hair that was stuck on the outside of a container used to store sponges for a long time. The design and functioning of the sponge cutting table as a source of particulate contaminants has not been considered. 2. The quality system is not aiming for continuous improvement; manufacturing processes are not designed in a way that product quality is achieved consistently: extensive corrective inspections are performed, repackaging of a significant number of units is routinely necessary due to quality defects, and rejection of significant parts of the batches is accepted as normal. An investigation initiated to improve the process is defective: contaminants removed during the visual inspection of unpackaged sponges are left out of the investigation, which is limited anyway to 2 batches only without proper justification. EU Non-Compliance Report: JINAN JINDA PHARMACEUTICAL CHEMISTRY CO., LTD., China: Nature of non-compliance : In total 18 deficiencies were identified by the inspection team, one of them was classified as critical and six as major. The critical observation was related to an unofficial and non-controlled storage area containing mainly raw materials and finished products which had been made inaccessible to inspectors as the door had been removed and replaced with a panel fixed with screws to the wall, which during the inspection the Company was requested to remove. The material stored in this area was to be managed outside of the Quality Assurance system and the investigation carried out by the inspection team concluded there was a serious risk of data falsification. One of the six major deficiencies was related to a very similar issue, as access to a locked garage was given to the inspection team only hours after requesting it. In both cases the explanations provided were not sound and different versions were given during the inspection. The remaining five major deficiencies were related to specific aspects of the Quality Assurance System with regards to training, cleaning validation, breaches of data integrity in the context of HPLC analysis, microbiological laboratory, qualification of contract manufacturer of a key intermediate of Nitrofurantoin production.
  44. 44. PHARMA UPTODAY 44 EU Non-Compliance Report: WUXI JIDA PHARMACEUTICAL CO., LTD, China Nature of non-compliance : The inspection was performed by GMP inspectors in relation to the manufacture of sterile glutathione sodium lyophilised object of a variation. The inspection was focused on site 1 and production workshop number 3. During the inspection 28 deficiencies were found, 15 of which were rated as major deficiencies. Major Deficiencies: In many production steps deviations were found regarding the sterility assurance and a risk of contamination of the product: a) Sampling room (deviations 14-15-16): the changing room was not designed in a suitable way to minimize the risk of contamination; the differential pressure between the areas maintained at different cleanliness grade was not monitored; the garments procedure was not in accordance to the principle of classified areas; b) Production areas (deviations 19-20-21-24): the pressure differential between adjacent areas at different cleanliness grade was not in compliance with the guidance value of the European good manufacturing practices; the maintenance and cleaning conditions of some production rooms were poor and not adequately handled; the particle counters in B class grade (i.e. freeze-dryers and capping room) were unsuitable located for the intended use; the API transfer from the mixer to aluminum tin did not exclude a risk of API contamination. c) Validation (deviation 7 from letter a to j): the validation approach for different activities was not correctly performed according to the GMP requirements and validation reports were not detailed (warehouse temperature mapping; holding time for sterilization of tools; stay-time in UV-pass box; maximum number of filters sterlisation (20) validation for the moist heat sterilizer used for the rubber stopper sterilization; validation for the dry heat steriliser used for the aluminium tin sterilisation; validation for LAF in weighing room; validation for the HVAC of the sampling room; validation for front-freezing room classification; validation report for the process simulation namely maximum filling time of loading the bulk product in freeze-dryers and maximum time of transferring API from mixer to aluminum tins and capping. d) Packaging and labeling (deviations 5-10-11-13): the management for the container closure system for sterile glutathione sodium freeze-dried was found lacking in some tests to guarantee the sterility assurance of the product; a ―wrong― and not-updated label was used as a standard to verify the shipping labels of API; in the API warehouse, the aluminum tins of sterile API were not sealed; the aluminum caps were not identified with a batch number loosing traceability. e) Laboratory testing (deviation 28): some deviations were found for the IR instrument, in particular the IR software had not a controlled access via ID and password and it was not forbidden to copy and rename a file.
  45. 45. PHARMA UPTODAY 45 f) Personnel behavior (deviations 2-7i(ii)-18-19): during the inspection, the inspectors’ team received inconsistent and conflicting answers on the same topic from both personnel and management; sometimes the answers seemed to be modified according to the inspectors’ requests. The documentation was showed in an ambiguous way as the examples: some layouts were replaced; some documentation was unrelated to the topic. Finally management did not comply with the clothing procedure during the inspection tour. EU Non-Compliance Report: PARABOLIC DRUGS LIMITED, India Nature of non-compliance : The quality management system was found to be seriously uncontrolled and deficient in all ―Principles‖ (except principle 2.13 and 2.14) reported in the EU- GMP requirements as evidenced by critical and major deviations found in the following areas: inadequate storage and control of documents and samples and material, falsification of documents and data, integrity and security of data in the QC laboratory, Change Control, Deviations management and Risk management. In total 27 deficiencies were found: 3 classified as Critical were found in the area of Documentation management system, Falsification and Security and integrity data; 7 classified as Major deficiencies were found in the area of QC, Personnel, Documentation and Change Control. FDA Warning letters US FDA Warning letter: Mahendra Chemicals, India The investigators observed specific deviations during the inspection, including, but not limited to, the following Failure to record activities at the time they are performed and destruction of original records a) Our investigators found that some of your operators used ―rough notes‖ (unbound, uncontrolled loose paper) to capture critical manufacturing data and then destroyed these original records after transcription into the batch production records. b) Additionally, our investigators found backdated batch production records dated February 10 to February 25, 2014, signed by your Production Manager and Technical Director in the ―Batch Manufacturing Record Reviewed [sic] by‖ section. The Technical Director stated that he was not in the facility on these dates and was ―countersigning‖ for another person who allegedly performed these review activities.
  46. 46. PHARMA UPTODAY 46 Failure to prevent unauthorized access or changes to data, and to provide adequate controls to prevent omission of data a) There is no assurance that you maintain complete electronic raw data for your Gas Chromatography (GC) instrument. FDA investigators observed multiple copies of raw data files in the recycle bin connected to the GC instrument QC-04 even in the presence of ―Do Not Delete Any Data‖ notes posted on two laboratory workstation computer monitors. b) Employees were allowed uncontrolled access to operating systems and data acquisition software tracking residual solvent, and test and moisture content. Our investigators noted that there was no password functionality to log into the operating system or the data acquisition software for the GC, the High Performance Liquid Chromatography (HPLC) instrument QC-17, or the Karl Fischer (KF) Titrator QC-13. c) HPLC SpinChrome and GC Lab Station data acquisition software lacked active audit trail functions to record changes in data, including original results, who made changes, and when. Check your area for …. Are lab investigations … thorough, identifying the root cause, and closed in a timely manner?
  47. 47. PHARMA UPTODAY 47 Regulations of the Month Subpart B--Organization and Personnel Sec. 211.25 Personnel qualifications. (a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them. (b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess. (c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product. Subpart B--Organization and Personnel Sec. 211.28 Personnel responsibilities. (a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.
  48. 48. PHARMA UPTODAY 48 Top Presentations of Pharma Uptoday · Presentation on data integrity in Pharmaceutical Industry · Data Integrity II - Chromatography data system (CDS) in Pharma · Good chromatographic practices · HPLC - Peak integration for chromatography · Good Laboratory Practices for Pharmaceutical Quality Control Laboratories · Laboratory Errors · Understand the importance of each step to minimise Laboratory errors · Sample preparation techniques of solid dosage forms · Investigating aberrant potency values in Pharma Analysis · All about Tablets (Pharma) Few Pharma Uptoday topics can be accessed from our website https://sites.google.com/site/pharmauptoday/ Few Pharma Uptoday presentations can be accessed from our website http://www.slideshare.net/skvemula To subscribe free online daily Newsletter write a mail to pharmauptoday@gmail.com with subject “Add mail”.

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