MONTHLY UPDATE - MARCH/APRIL 2014 IPQ WWW.IPQPUBS.COM INTERNATIONAL PHARMACEUTICAL QUALITY Inside the Global Regulatory Dialogue VOL. 5, NO. 3 GMP/INSPECTION • Drug GMP Warning Letters from 2012 – Q1 2014 Show FDA’s Enforcement Focus Shifting Overseas: Foreign Labs Draw Particular Attention.............................................................................................................3 • FDA Data Integrity Findings Continue at Indian Firms, Highlighting Challenges in Changing a Facility’s Quality Culture.....................................................................................................................................19 • Component Testing Gains Prominence in Drug Product GMP Warning Letters as FDA Focus Intensi- fies on OTC Topicals and Upstream Supply Chain.........................................................................................30 • Wave of FDA Warning Letters to Injectable Compounders in Q1 2014 Follows 2013 Inspection Blitz and Legislative Empowerment; Recipients Among Those Applying for Outsourcing Status..................36 • Comments on FDA’s Draft Compounding Guidances Reflect Complex Factors and Varied Stake- holders Involved...................................................................................................................................................40 • Compounding Drivers and Problems Dissected by Merck Pharmacy Expert at April PDA Annual Meeting...................................................................................................................................................................45 UNITED STATES UPDATES IN BRIEF - p. 57 U.S.: • Comments on NDA/ANDA Processes • Global Ingredient Archival System • BA/BE Draft Guidance • Vial Overfills • Orphan MAb Sameness • ISPE Metrics Pilot • Geo-spatial Mapping EUROPE: • Drug Approval Fast Track •Sterilization Processes • Variation Stability Requirements • UK Biologics Research Center • MHRA 2014-2015 Business Plan • Advanced Therapies Regulation • Post-authorization Q&A • EDQM CEP Policy • EDQM Anti-Counterfeiting Database • Applications/Advice Procedures • Immungenicity Concept Paper • GDP Q&A • Quality System GMPs INTERNATIONAL: • Brazil Withdrawal Notification • EMA/TGA Orphan Drug Collaboration • FDA/EMA QbD Initiative • WHO Hold Times EUROPE CMC/REVIEW & GMP/INSPECTION • ICH Q8-11 Oriented Submission and GMP Expectations for Process Validation and Other Quality Issues Taking Shape in Europe..........................................................................................................50
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MONTHLY UPDATE - MARCH/APRIL 2014
IPQWWW.IPQPUBS.COM
INTERNATIONAL PHARMACEUTICAL QUALITY
Inside the Global Regulatory Dialogue
VOL. 5, NO. 3
GMP/INSPECTION
• Drug GMP Warning Letters from 2012 – Q1 2014 Show FDA’s Enforcement Focus Shifting Overseas:Foreign Labs Draw Particular Attention.............................................................................................................3
• FDA Data Integrity Findings Continue at Indian Firms, Highlighting Challenges in Changing aFacility’s Quality Culture.....................................................................................................................................19
• Component Testing Gains Prominence in Drug Product GMP Warning Letters as FDA Focus Intensi-fies on OTC Topicals and Upstream Supply Chain.........................................................................................30
• Wave of FDA Warning Letters to Injectable Compounders in Q1 2014 Follows 2013 Inspection Blitzand Legislative Empowerment; Recipients Among Those Applying for Outsourcing Status..................36
• Comments on FDA’s Draft Compounding Guidances Reflect Complex Factors and Varied Stake-holders Involved...................................................................................................................................................40
• Compounding Drivers and Problems Dissected by Merck Pharmacy Expert at April PDA AnnualMeeting...................................................................................................................................................................45
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UPDATES IN BRIEF - p. 57
U.S.: • Comments on NDA/ANDA Processes • Global Ingredient Archival System • BA/BE Draft Guidance • Vial Overfills • Orphan MAb Sameness • ISPE Metrics Pilot • Geo-spatial MappingEUROPE: • Drug Approval Fast Track •Sterilization Processes • Variation Stability Requirements • UK Biologics Research Center • MHRA 2014-2015 Business Plan • Advanced Therapies Regulation • Post-authorization Q&A • EDQM CEP Policy • EDQM Anti-Counterfeiting Database • Applications/Advice Procedures • ImmungenicityConcept Paper • GDP Q&A • Quality System GMPsINTERNATIONAL: • Brazil Withdrawal Notification • EMA/TGA Orphan Drug Collaboration • FDA/EMA QbD Initiative • WHO Hold Times
EUROPE
CMC/REVIEW & GMP/INSPECTION
• ICH Q8-11 Oriented Submission and GMP Expectations for Process Validation and OtherQuality Issues Taking Shape in Europe..........................................................................................................50
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EDITOR’s NOTE: Welcome to IPQ’s “Monthly Update” on key CMC/GMP developments in the US, Europe, and internationally. The IPQ family of publications includes “The News in Depth” and”Updates in Brief” on our website as they occur, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.” IPQ’s suite of offerings support our mission of helping readers understand, engage in and respond to the dialogue and developments around evolving and harmonizing the regulation of drug and biologic quality and manufacturing. Subscribers and license holders to IPQ have access to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further information.
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Warning Letters from 2012 – Q1 2014 Show FDA’s GMP Enforcement Focus Shifting Overseas; Foreign Labs Draw Particular Attention
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An analysis of FDA drug GMP warning letters issued since the beginning of 2012 highlights the agency’s increasing focus on enforcement outside the US – and on laboratory practices at foreign facilities, in particular.
In 2012, for the first time, foreign warnings began outpacing those issued domestically. Between 2012 and the first quarter of 2014, 47 drug GMP warning letters were issued internationally compared to 43 in the U.S.
The roadmap for an increased enforcement effort overseas was laid out in FDA’s “Beyond Our Borders” initiative (see IPQ Monthly Update” September 2011, pp. 27-34), and given further support by the passage in mid-2012 of the FDA Safety and Innovation Act (FDASIA), and its generic drug user fee and supply chain provisions, in particular (see IPQ “Monthly Update” January 2014, pp. 13-20).
FDA’s current budget proposal indicates that its effort to beef up enforcement abroad is accelerating. “To achieve greater parity,” the agency is projecting a significant shift in resources from domestic to foreign drug GMP inspections beginning in FY 2014.
FDA is targeting a 40% reduction in the number of routine domestic GMP inspections (not including pre-approval) from 967 in FY 2013 to 591 in both FY 2014 and FY 2015, and a 30% increase in foreign GMP inspections from 604 in FY 2013 to 843 in each of the two succeeding years.
Foreign API, Topical and Injectable Letters Outpace Domestic
The 2012 through Q1 2014 warning letter numbers would have been even more skewed toward the international arena if FDA’s inspection crackdown on large scale injectable compounders in the US had not been in full swing in the wake of the meningitis crisis that surfaced in the fall of 2012 (see IPQ Special Report November 2012, and story on p. 36).
Altogether almost 20% of drug GMP warnings issued in this timeframe went to sterile compounders across the US, including nine of the 11 that went out in Q1 2014.
The early-2014 bolus reflects the passage of the Drug Quality and Safety Act (DQSA) late in 2013. The compounding provisions of DQSA in Title 1 of the act clarified and strengthened FDA’s ability to take enforcement action
against the large-scale compounders on both CGMP and drug approval non-compliance grounds. The act also defines a new “outsourcer” category, which will give those that qualify relief from the drug approval and labeling rules, but not from relevant drug GMP requirements (ibid.). Title 2 of DQSA sets up the ground rules for establishing a tracking and tracing system for prescription drugs.
As would be expected, weighted particularly heavily on the international side were the warning letters that went out to API manufacturers – 12 out of 15 of these addressed foreign facilities. However, notably, warning letters were also more numerous abroad to finished dosage manufacturers making both injectables (11 of 17) and topicals (14 of 22).
Surprisingly, topical manufacturers have been the leading target of warning letters since 2012 – eclipsing in number those issued to oral, injectable and API manufacturers (see story on p. 30).
The compliance attention on OTC topicals in the recent warning letter data reflects, in part, FDA’s ongoing effort to get non-monograph-compliant/unapproved drugs off the market – an effort that has been expanding abroad, as the warning letter data indicates.
India Plants Flagged by FDA and EMA
An analysis of the foreign letters by country shows that India received nearly 30% of the letters issued abroad (13 of 48), while Canada was second with 12%, and Mexico third with 10% (see box below).
accounting for 14 of the 34, or about 40%. China was second with 10 NCSs, or about 30% of the 2013 total. Only 3% (three of 92) of FDA’s GMP warning letter total in 2012-2014 involved Chinese facilities. Two facilities in South Korea and the UK were given NCS status, with one plant in each of seven other non-U.S. countries appearing on the list.
The database also contains a section for good distribution practice (GDP) non-compliance statements. Only one GDP-related NCS appears, resulting from a March, 2014 inspection of a wholesaler in the Czech Republic, MaxPharma. The NCS states that the firm does not comply with GDP requirements in that it does not have “authorized storage facilities,” did not apply for a variation to the distribution authorization, and did not report required data.
Foreign Labs in Focus
FDA warning letters provide a portal into the deeper regulatory trends impacting pharmaceutical manufacturers, and a review of the 2012-14 cohort reveals some significant shifts in the enforcement sands.
Funneling from what investigators uncover on the shop floors through FDA’s compliance management to company executives, the concerns addressed in the warning letters indicate where the greatest risks to product quality lie across the industry and where the agency will, in turn, be placing its attention to try and get them addressed. In one sense, warning letters reflect FDA enforcement priorities – in another, they drive them.
Emerging into high relief as FDA increases its attention on the international arena are significant gaps in how firms are handling their laboratory operations and data. Following the dialectic process, the mounting evidence is driving the agency to further ramp up its lab focus abroad – and domestically as well.
What the investigators are finding both at the dosage and API levels abroad is that the analytical methods being used are not always validated.
They are also finding that controls are not in place to assure that problematic results are recognized and dealt with – and not buried, discarded or manipulated – and that the required tests are actually being performed as recorded.
Given the frequency of the agency’s findings that those controls are lacking – particularly in India, which supplies a significant percentage of the APIs, generics and OTC products on the US market – laboratory scrutiny will continue to be central on FDA’s inspection radar screen.
Nearly half of the Indian firms receiving letters produce APIs. Sharpening FDA’s enforcement focus on India has been the recurrent findings of data integrity issues at Indian facilities (see story on p. 19). Of the 13 warning letters issued to Indian plants since 2012, seven specifically address a lack of integrity of their records, procedures, and/or interactions with FDA investigators.
Notably, none of the three warning letters issued to firms in China specifically reference data integrity. All three address topical production.
The Chinese firms receiving warning letters, all in 2012, were: ● Jianerkang Medical Dressing, Jintan City, Jiangsu (June)● Shanghai Huhui Daily Use Chemical Products, Shanghai(November), and ● Fercy Personal Care Products, Zhejiang (September).
Of concern at all three firms was the approval of procedures and methods by the quality unit, investigations, and process/sterilization validation. Shanghai and Fercy were also cited for selling unapproved drugs, and for the lack of facility registration.
Another significant concern highlighted in the warning letter to Fercy was the firm’s decision to terminate the inspection that resulted in the warning letter three days earlier than previously agreed.
In December 2013, EMA updated the public version of its EudraGMDP database to include GMP non-compliance statements (NCSs). In 2013, there were 34 facilities added to the list, making sterile and non-sterile products and APIs.
India also led in the number of NCSs listed by EMA in 2013 –
Foreign Warning Letters 2012-2014The following is a breakdown of the foreign drug GMP warning letters issued from 2012 through Q1 2014 by the country where the facility was located. Countries in which only one letter was received – not included below – were Australia, Austria, Denmark, Ireland, Italy, Jamaica, Poland, Serbia, and United Arab Emirates (UAE).
0
2
4
6
8
10
12
14
India
Canad
a
Mexico
China
German
ySpain
Hong Kong
Japan
Taiw
an
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methods provisions of 211.165(e).
While not addressed by Thoma, FDA’s concern with the evaluation of incoming components has been especially noticeable in the large number of GMP warning letters that have gone out to OTC topical manufacturers over the past few years.
The focus on GMP control at topical producers – and on component testing, in particular – reflects the number of ingredients topicals contain and the potential for microbial contamination to find its way into the products, which may be used on or near wounds. Accordingly, cleaning and stability programs have been other key areas of concern in the topical letters.
Method Validation For Vaccine Testing of Concern at Sanofi
in a July 2012 warning letter addressing vaccine production at Sanofi Pasteur, concern about the validation of lab methods used to detect mold and yeast was juxtaposed against internal non-conformance reports citing 58 instances of possible mold detection in an 18-month period. The letter addresses the findings during inspections conducted in March-April 2012 of Sanofi Pasteur vaccine sites in Toronto, Canada, and Marcy l’Etoile, France.
Regarding the Toronto findings, the letter maintains that sterility for “all lots” of TheraCys BCG live vaccine manufactured since the last successful validation of the method in 2000 “cannot be assured.”
Attempted re-validation of the method conducted from March through April 2012 failed acceptance criteria, indicating “there is no assurance that the test method is capable of detecting yeast and/or mold in the product.” The BCG vaccine is used in the prevention of tuberculosis.
Investigators pointed to “no less than 58 documented non-conformances relating to the isolation of mold” in aseptic processing areas of the Toronto facility since August 2010.
The letter also expressed other sterility-related concerns, including vial handling in the aseptic processing area, allowing facility personnel and an FDA investigator to enter a washing and sterilizing area directly from a live vaccine testing area, and “nesting birds” in the air handling intake units.
CBER Office of Compliance Director Mary Malarkey included, as part of the warning letter, 20 specific observations from the 483 issued to the Toronto plant along with commentary on the responses – finding many of them inadequate – and requests for additional information.
Finding Lab Issues Require Expertise
The greater focus on lab operations in overseas inspections reflects, in part, the broader review that investigators employ when applying FDA’s system-based inspection approach overseas. Foreign inspections generally cover all six systems – quality, laboratory, production, materials management,facilities and equipment, and packaging and labeling – as compared to those domestically, which may only focus on the quality system and one of the other five, not necessarily including the lab.
Another factor is the frequent participation in international inspections of chemists and microbiologists, who are more experienced in evaluating lab operations and data.
In a presentation at the University of Georgia/FDA International GMP Conference in Athens, GA in mid-March, Office of Regulatory Affairs (ORA) National Pharmaceutical Inspection Expert Sharon Thoma commented on this lab focus in the foreign context.
Noting that “a lot of investigators do not feel comfortable in the laboratories” and may avoid them, Thoma said that she is “excited to see” that FDA is looking for and finding more of these lab issues. “I think that you are going to see that more and more as we get more scientifically based,” she said.
The agency investigator went on to explain how the concern with lab methods and data integrity is playing out in a notable surge in enforcement attention by FDA on incoming component testing (see story on p. 30). Her review of the FY 2012 and 2013 foreign warning letters found that component testing (211.84(e)) was the second leading cite (in a tie with process validation (211.110(a)), behind the lab
FDA International Pharmaceutical CGMP Actions
Action Type FY 2010 FY 2011 FY 2012 FY 2013
Inspection Reports Received
439 470 680 743
Insp. Report Reviews, Completed
407 427 516 566
Warning Letters Issued 12 20 23 26
Untitled Letters Issued 4 5 1 6
Import Alerts—CGMP Violations (66-40)
3 16 22 21
Import Alerts resulting from foreign regulatory authority inspections
-- -- 1 2
Import Alerts—Heparin (55-03)
-- -- 17 --
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complete evaluation to determine the improvements that you will need to make at your firm in order to meet the CGMP requirements for the manufacture of OTC drug products.”
Lab Records Also at Issue Overseas
Recent examples of lab problems related to 211.194(a), which requires lab records to be complete, can be found in warning letters to Taiwan-based Beanne Chemical (December 2012), Canada-based Apotex (February 2013), concerning its Toronto plant, and India-based Wockhardt (July 2013). Beanne and Apotex produce sterile products at the plants referenced in the letters, while Wockhardt was cited for solid oral dose manufacturing at its facility in Aurangabad, India.
Of concern at Wockhardt was a failure to document all lab tests performed and the integrity of the data produced. Integrity problems were prominent outside the lab as well in the warning letter (see story on p. 19).
At Beanne, investigators expressed concern that raw data used to support the release of finished product lots was not available.
During the inspection, raw data from the finished product testing described in the firm’s certificates of analysis was requested. However, the firm’s management stated that it did not maintain records of the raw data.
“We are concerned,” the letter to Beanne emphasized, “that the certificates of analysis include test results for total aerobic microbial count, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, arsenic, lead, mercury, and skin irritation, but no raw data is available to ensure that the analyses were conducted correctly or that the results reported were within specifications.”
Accuracy of lab records related to environmental monitoring (EM) was a focal point in the August 2012 inspection of the Apotex site in Toronto that led to the warning letter.
An FDA investigator observed a microbiologist reading an EM plate and recording a result of zero. The investigator, however, noted one colony forming unit (CFU) on the plate. Although the firm’s microbiologist corrected the observation when the error was pointed out, no further action was taken to determine the impact of the finding on the finished product.
Failure to document positive results for a microbial plate, Acting Director of FDA’s Office of Manufacturing and Product Quality Michael Smedley noted in the letter, “raises concerns about the accurate reporting of results in your
Two 483 observations from the Marcy l’Etoile, France plant were also addressed related to the production of haemophilus conjugated vaccine. Requested by Malarkey were progress reports on finding root causes and implementing corrective actions for lots that had extended filtration times and displayed “an adverse trend” on bacterial content.
Sterility concerns were also cited by Australia's at the Toronto facility a month after the 2012 FDA inspection that prompted the warning letter. A recall of four lots of the TB vaccine followed the two inspections.
Sanofi shut down part of the Toronto plant for remediation, which resulted in a shortage of the BCG vaccine that the company does not anticipate being able to resolve until the end of 2014.
In the wake of the compliance, recall and shortage problems, the firm brought on board industry veteran and former Genentech VP Anders Vinther as Chief Quality Officer, a position that reports to the CEO. Vinther has played an important role in advancing quality system concepts and their application in the biotech industry, and has served in various capacities at PDA, including as the association’s Chairman of the Board.
Mexican Oral Dose Firm Also Cited for Methods
Method validation also came up on the OTC side in the context of method specificity for pediatric tablets manufactured at Mexico’s Selder S.A.
An April 2013 warning letter asserts that the firm did not conduct specificity testing as part of its validation for an HPLC method used to test “Children’s XL-3 Chewable Tablets” – an OTC acetaminophen product.
The agency requested that the firm include in its response a detailed review of all analytical test methods it employs “to ensure that they have been properly validated and verified that they are adequate for actual conditions of use.” Also requested was a list of revisions made to the analytical methods as a result of the review.
Other deficiencies investigators uncovered caused the agency to question the effectiveness of the Mexican firm’s quality system “to achieve overall compliance with CGMP” at the facility.
Specifically noted were “several instances” of equipment qualification that was lacking and “incomplete” laboratory data. FDA’s Office of Manufacturing and Product Quality (OMPQ) Director Steve Lynn asked Selder to “seek the advice of a third-party consultant for assistance with a
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related to reports from finished drug manufacturers, which have alerted the agency to “difficulties or problems or failures” in their product that they attribute to the API.
“I would say in the last two or three years we have seen a relatively large increase in the number of inspections that were generated in that way,” she commented.
The issues pointed to by D’Orazio are also being reviewed by FDA at API contract testing labs. A March 2012 warning letter to an API testing lab in Cucutitlan, Mexico, UNAM, included citations in two of the problem areas she highlighted – OOS investigations and documentation of controls.
Investigators asserted that the firm had no procedure in place for investigating OOS results. The letter requested that in its response UNAM include an OOS investigation procedure along with the associated training documentation. FDA suggested that the OOS procedure include: ● a requirement for initiation of an investigation “without delay” ● an evaluation of the root cause of the result ● justification of any re-sampling and/or retesting ● a system for assuring corrective actions are implemented, and ● notification to the firm’s client of any OOS result.
The letter also points to the firm’s lack of documentation of API samples tested on its atomic absorption spectrophotometer for a 12-year period from 1999 through 2011, and an associated lab notebook that did not contain the raw data from the tests. Also of concern was a lack of records indicating routine calibration of the spectrophotometer as well as of an HPLC unit and an analytical balance.
Two Big Pharma API Plants Draw Warnings
While most of the drug GMP warning letters since 2012
records.” He added that “accurate and reliable microbial data management” is “essential” to support the “reliability” of aseptic manufacturing.
Inadequate Lab Controls Top API Findings
Lab controls have also been found lacking at overseas API manufacturers.
At an ICH Q7 training workshop co-sponsored by PIC/S and PDA in February 2014 in Bethesda, Maryland, FDA investigator and pre-approval manager Karen D’Orazio discussed the regulatory framework for API inspections, current FDA thinking and guidance regarding APIs, and the most common deficiencies the agency is seeing in API inspections (see box below).
The top citation for APIs, she pointed out, is inadequate lab controls. The areas in which the agency is seeing the most lab control deficiencies include: ● method validation ● scientifically sound and appropriate specs and test procedures ● investigation of out-of-specification (OOS) results ● documentation of controls and product performance, and ● the stability testing program.
D’Orazio commented that she has seen “the same types of issues” in pre-approval as well as routine inspections for both APIs and finished drugs.
The agency investigator also discussed “directed inspections” for API manufacturers resulting from problems with APIs that finished dosage firms have reported to the agency.
In addition to being an inspector, D’Orazio is also involved in FDA’s field alert program. In that capacity, she has “recently” seen “a fair number” of directed inspections
FDA’S D’ORAZIO ON API REGULATION AND INSPECTION
At an ICH Q7 training workshop co-sponsored by PIC/S and PDA in February 2014, FDA investigator and pre-approval manager Karen D’Orazio discussed the regulatory framework for API inspections, current FDA thinking and guidance regarding APIs, and the most common deficiencies the agency is seeing in API in-spections.
Our authority to regulate API manufacturers derives from the [Food, Drug and Cosmetic] Act itself, and from section 704(a)(1). There it authorizes the FDA to do factory inspections if the drugs are manufactured for introduction into interstate commerce. This is important. It doesn’t specifically limit drug production sites to U.S. territory, which is particularly important given the global impact of our inspections today.
Also, in section 201(b) of the Act, interstate commerce is defined as commerce between any state and any place outside thereof. So products outside the U.S. and the firms producing them are considered to be in interstate commerce.
So now we know what we can inspect. But what are drugs themselves? How do we define drugs? From the act,
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section 201(G) defines drugs as ‘articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease…intended to affect the structure or any function of the body.’ So the definition is not limited to drug products, i.e. finished drug forms. This is important for our discussion of APIs.
The FDA definition of bulk drug components comes from the preamble to the 1978 revisions to the cGMP regulations. Bulk drug components are defined as ‘ingredients intended for use in the manufacture of a drug product.’ One more definition from the FDA comes from our 21CFR part 210, which defines an active ingredient as ‘any component intended to furnish pharmacologic effect, and it includes components that may undergo chemical change in the manufacture of a drug product.’
One more definition of note then is the Q7A definition of an active pharmaceutical ingredient: ‘Any substance or mixture of substances intended to be used in manufacture of a drug product...intended to furnish pharmacological activity or other direct effect.’
Knowing this, knowing what FDA can inspect, and knowing what we define a drug to be – not just a finished drug product but also an active ingredient – then we go into our actual regulation of the APIs.
They are subject primarily to the adulteration provisions of section 501(a)(2)(B) of the act, which requires all drugs to be manufactured in conformance with good manufacturing practices. This is important because our regulations for drugs, 21CFR 210 and 211, really don’t apply to APIs, except in that small case of sterile APIs after the point of sterilization.
Also, the cell culture fermentation uses language from related FDA regulations and that is discussed in section 18 of Q7. So for us as regulators, it is a very nuanced use of 211 in terms of informing us as to what good manufacturing practice is. In 2001, FDA adopted Q7 as a guidance document and continues to use Q7 as representative of FDA thinking on the subject of APIs.
Another guidance document that is used internally and that is open to the public domain is our active pharmaceutical ingredients process inspections guidance, which is 7356.002F. In that you find ‘incorporate a systems-based inspection approach.’ It was implemented in 2006, and there were some minor changes in 2013. One thing of note for that particular guidance is that it doesn’t cover biotechnology derived APIs – for that you need to go to another document, which is ‘inspections of biologically licensed therapeutic drug products.’
I think the take home message for this is that we really do not have much in the way of regulations – a really small amount of regulation – but everything derives from the act itself.
API Inspections
When we do our onsite inspections of APIs, they tend to fall into several categories. One would be a surveillance inspection, which is a routine GMP inspection and part of our work plan. Another would be a pre-approval inspection. And the other could be a directed inspection. The types of directed inspections that we might have would be a follow-up to a regulatory action like a warning letter.
The other type of directed inspection that I have been more familiar with – because, in addition to being an inspector, I also run our field alert program – we have actually seen recently a fair number of directed inspections related to reports from finished drug manufacturers who have alerted us to the fact that APIs might have been the cause of
difficulties or problems or failures in their finished drug product. I would say in the last two or three years we have seen a relatively large increase in the number of inspections that were generated in that way.
The other thing about onsite inspections of APIs is, because the primary areas where they are manufactured are out of the U.S., 70-90% of our inspections are out of country for APIs. And pre-notification is required for the foreign inspections only.
Our onsite inspections are conducted as GMP qualifying inspections of APIs as they are assigned to us. They may be product-specific. And really what we are trying to do is use a systems coverage to determine the ability of the firm to produce any API – using the same systems of controls and procedures, whether it be for chemical synthesis, fermentation, biotech, etc.
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have gone to smaller firms and compounders, a half-dozen of them were issued to big pharma. Four of these related to injectable manufacturing and two encompassed API production.
The API letters went to Boehringer Ingelheim (BI) in May 2013 for an API, oral solid, and inhalation dosage form site in Germany, and to SmithKline Beecham (SKB) – a GlaxoSmithKline (GSK) subsidiary – in March 2014, for an API site in Ireland. Both cited two areas D’Orazio discussed as common problem areas for APIs – investigations and quality unit approval or rejection of batches.
Notably, both letters focused on contamination of APIs – particulates at BI, and “industrial waste” at SKB – and concerns with the related investigations.
The warning letter to BI asserts that while the firm was aware of “extrinsic foreign particles” in multiple API lots produced in 2008 and 2009, the decision was made to use the lots to fill capsules and produce final dosage forms. FDA expresses concern that BI did not begin “a formal action to mitigate the presence of foreign particles” in its API until 2012.
The letter also points to a complaint BI received from a cus tomer that identified foreign particles in an API batch it received, manufactured in 2009, and the firm’s conclusion that the complaint was “not confirmed” in spite of internal evidence of the particulate contamination. A September 2011 complaint
by a customer for particles was classified as “confirmed,” leading the agency to question the designation criteria used.
“Your conclusion of ‘confirmed’ or ‘not confirmed’ is inconsistent,” the letter emphasizes, “as both complaints were related to the presence of foreign particles found in your APIs, but your final conclusions were different.” The agency requested that the firm provide it with the corrective actions taken to prevent foreign particle contamination in its APIs.
At SKB’s site in Ireland, the focus was on API batches that were contaminated with material from a “pharmaceutical waste tank,” which contained APIs, intermediates, and solvents, and the adequacy of the firm’s investigation and disposition of the lots.
FDA compliance official Lynn expressed concern in the letter that different batches were tested for the contamination by different analytical methods, resulting in some batches being distributed while others were rejected. While the standard analytical testing performed on some batches did not detect “significant” amounts of the contaminants, leading to the lots being approved, the additional testing on other lots revealed that they had been exposed to significant amounts of the contaminants, and those lots were rejected.
Also at issue was the firm’s SOP regarding notification to customers of deviations that have the potential to impact
Top Five Citation Areas for APIs
Lab controls● method validation ● scientifically sound and appropriate specs and test procedures ● OOS investiga-tions ● documenting lab controls at the time of performance ● stability testing
Quality system● approval or rejection of APIs ● approval of quality related documents ● complaint investigations ●regular quality reviews ● evaluation of the potential impact of proposed changes on the quality of APIs.
Equipment cleaning, maintenance & validation● equipment maintenance ● cleaning procedures ● equipment validation ● cleaning, storage, sanitiza-tion, and sterilization to prevent contamination or carry over ● qualification of critical equipment
Records and reports● batch production records ● inclusion of complete data derived from all tests in the lab control records
SOPs● written procedures for production activities, quality responsibilities, laboratory processes, materialsmanagement, and laboratory controls
D’Orazio went on to discuss the top five GMP deficiencies seen by agency investigators in GMP inspections. She noted that as a pre-approval inspection (PAI) manager, she has seen “the same types of issues” in PAIs for finished drugs as well. Specific concerns within the five areas cited by D’Orazio are listed.
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Atlanta District Director John Gridley advised the firm that a “recent” inspection at another Baxter facility also cited a pattern of inadequate corrections and interventions. “While the response to that location’s deficiencies appears adequate, we expect appropriate correction at all Baxter facilities in this critical area,” he emphasized.
India Plant Adds to Hospira’s Compliance Problems
In May 2013, Hospira’s injectable manufacturing plant in Sriperumburdur India was warned for violations uncovered during an October 2012 inspection period. The problems were similar to those found at its beleaguered Rocky Mount facility earlier that year (see IPQ “Monthly Update” Jan./Feb. 2013, pp. 2-11).
Included were citations related to aseptic technique and other personnel practices, process validation, smoke studies, and media fills.
Compliance official Smedley expressed his concern in the letter on the Indian site regarding the similarity of the violations, and requested that the firm provide “a current global corrective action plan” for domestic and foreign Hospira facilities. He advised that the plan should include “a comprehensive training module on aseptic process techniques for all employees involved in aseptic process operations” and how the firm will measure the effectiveness of the training.
Agency concerns at the Rocky Mount plant, expressed in lengthy 483s since 2008 and underscored in a warning letter in April, 2010 (see IPQ “Monthly Update” September 2010, pp. 14-15) would typically have resulted in a plant closing, potentially under a consent decree, until the remediation could be assured by the agency.
However, the role Hospira plays in supplying medically necessary injectables and the threat to the healthcare system if that supply were disrupted led the agency to work with the company in achieving the overhaul while production continued.
The firm took a quality-by-design (QbD) oriented approach to compliance remediation and quality improvement at the North Carolina injectable manufacturing facility – focusing more heavily on identifying and monitoring critical process steps than on reviewing batch records (see IPQ “Monthly Update” Jan./Feb. 2013, pp. 2-11).
In an early February 2014 conference call on 2013 earnings, Hospira CEO Michael Ball said that his firms was “recently verbally advised by FDA that the status of our Austin facility and the pharmaceutical operations at Rocky Mount have been changed to VAI [voluntary action indicated].” Subsequent to the 2010 warning letter, he said, the company has
product quality and the firm’s choice not to “escalate” the contamination event by notifying its customers. “We are concerned that your firm does not consider the entry of pharmaceutical waste streams into your manufacturing process a significant deviation with a potential quality impact,” the agency emphasized.
Rounding out SKB’s warning letter were citations for chromatograms in which impurity peaks were “ignored” and not investigate by lab analysts, and process validations that were approved using non-consecutive lots when three consecutive lots, as mandated by the firm’s procedure, could not be achieved.
Baxter Injectable Plants Cited In NC & PR
Baxter drew a warning letter in May 2013 addressing findings at two of its injectable facilities – at its Marion, North Carolina, plant in late 2012, and at its Jayuya, Puerto Rico plant in early 2013.
FDA noted in both cases that there were repeat observations and that similar concerns had been found at other Baxter facilities.
At the North Carolina plant, agency investigators found “numerous” HEPA filters, supporting grid work, filter screens, and screen tracks, that contained “varying amounts of discolored areas, chipping paint, multicolored coalescing droplets, and clumps of dark material that FDA testing later revealed was mold.”
The agency inspectors asserted that maintenance personnel had documented “possible mold” on the “clean” side of HEPA filters supplying air to large volume parenteral production lines “at least as far back as July 2010,” but that no samples had been taken by the firm to determine what the material was. This was a repeat observation from an inspection at the same plant earlier in 2012.
In focus at Baxter’s Puerto Rico plant were the adequacy of investigations, manufacturing defects that could lead to compromised product sterility, and late field alert reports.
FDA pointed out in the 2013 letter that its concerns regarding investigations into sterility compromises in large volume parenteral (LVP) bags that were the subject of customer complaints and a product recall was a repeat citation from a 2011 warning letter. Cited were “numerous” open investigations regarding foreign material found in the bags that purported to be sterile.
Also at issue in the 2013 letter were consumer complaints identifying at least ten membrane leaks and 155 inadequately-fitting blue caps on the LVP bags during the period of November 2011 to March 2013. The letter characterized these as “critical defects” that can impact the sterility and stability of the products.
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invested $200 million in remediating the North Carolina plant.
Since the conference call, Hospira has announced injectable product recalls and recall extensions for a variety of products and reasons, including particulates found inside vials identified either by the company or by customers. The notices do not indicate at which Hospira site the products were manufactured.
Included in the recalls were:
● seven lots of injectable propofol, due to a glass defectlocated on the interior neck of the vial and free-floating metal particulates identified from a retained sample
● one lot of injectable lidocaine, due to a confirmed
customer report of orange and black particulate within the solution and embedded within the glass vial, identified by Hospira as iron oxide
● one lot of a preservative-free bupivacaine injection,due to a confirmed customer report of discolored solution with visible particles embedded in the glass as well as discolored solution, and
● one lot of preservative-free morphine injection, aftercustomer reports of either a loose crimp or no crimp on the flip-top vial.
COMMISSIONER HAMBURG ON THE IMPACT OF GLOBALIZATION ON FDA
At the opening session of FDLI’s annual meeting in Washington, D.C. in late April, FDA Commissioner Mar-garet Hamburg highlighted the significant changes the agency is making to expand its effectiveness in the global arena.
We have a lot on our plate, but across all of our domains of activity, the challenges get ever more complex as we must also grapple with our dramatically changing global marketplace. This change, in which the foods we eat and the medicines and medical devices we use increasingly come – in whole or part – from countries other than our own, has enormous ramifications for the work FDA does, and the people we work to protect.
And the numbers are astounding. 50% of fresh fruits and nuts, 20% of vegetables, and over 80 % of seafood consumed in America comes from abroad. Similarly, 40% of finished drugs come from outside our borders, and 80% of active ingredients manufacturers are located outside the US. Further, half of all medical devices are imported. And the volume of imports only continues to rise.
The fundamental shifts that are taking place as a result of globalization have huge implications for our ability to ensure the safety and quality of products manufactured elsewhere and the integrity of supply chains as those products move through an increasingly complex network of producers, manufacturers, packagers, distributors, exporters and importers. I would argue that this transformation also comes with huge economic and national security challenges as well.
As for FDA, we have already begun to reorganize our structure and transform from a domestic agency operating in a globalized world to a truly global agency fully prepared for a complex regulatory environment that takes into account the risks across a product’s life. This requires new reliance on enhanced intelligence, information and workload sharing with the help of regulatory partners, data-driven risk analytics, and allocation of resources achieved through public and private partnerships.
Most importantly, our job requires greater coordination of regulatory standards and practices across nations to ensure safety and quality, regardless of where a product is produced. We are working through bilateral and multilateral agreements, as well as through international organizations, specialized partnerships and various coordinating bodies. And at the highest levels, we have embarked on creating a new model or framework for global governance.
But specifically with respect to our work at FDA, much has happened in recent years. We have greatly enhanced our ability to do targeted border screening as products come in, using a computer driven, risk-based program called PREDICT to identify imports that need fuller examination versus those commodities at low risk that can proceed through.
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But that alone is not enough. We must work to enhance safety and quality long before these products reach our shores. We have enhanced overseas inspections and now have FDA offices in many parts of the world. This is proving very beneficial, but again, we must do more. We cannot inspect our way to safety with some 300,000 facilities in about 150 countries making products for export to the United States that we must oversee.
That is why the collaboration with both industry and our regulatory counterparts is increasingly vital. The rapid and profound rise of global commerce and trade requires that we continue to evolve and meet new demands. We can take comfort in the knowledge that we have significantly strengthened our ability to respond to these challenges and know where and how we must do more.
Similarly, the rapid advances in science and technology offer great opportunity but place new and evolving demands on us and the products we regulate.
Understanding the seriousness of these challenges – structural, scientific, economic, and global – is one reason why, when I took over as Commissioner, I could not settle for incremental changes in how FDA intends to conduct business for the 21st century. I am confident that the changes we are putting in place are sufficiently important and on track to survive well into the future. I believe that they are, in fact, absolutely essential.
And so we will continue to implement changes that fundamentally transform how we address these challenges before us, how our agency interacts with regulated industry and other stakeholders, and how the public understands and supports the mission of this important and unique agency.
It will require the work not just of the FDA, but of partners such as FDLI, to ensure the continuing alignment of our public health and medical care mission with the important regulatory and legal framework. I look forward to our ongoing work together, with continuity of purpose, renewed commitment to key principles, and a sense of the dynamic and changing world we live in that demands flexibility, resilience and an eye to the future.
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FDA Drug GMP Warning Letters Issued in �01�-Q1�01�
The following is a chronological listing of all 92 of the drug GMP warning letters issued between the begin-ning of 2012 and the first quarter of 2014, categorized into U.S. and International. The key concerns that each of the warning letters address and links to the letters themselves are provided.
United States (2014) Company Name Loca�on Le�er Date Product Type Areas Cited Pentec Health Boothwyn,
PA 03/07/14 Compounded • Sanitary condi�ons • Microbial control SOPs •
CAPA
Village Fer�lity Pharmacy
Waltham, MA
02/28/14 Compounded • Microbial control SOPs • Environmentalmonitoring • Personnel evalua�on • Equipment tes�ng • Drug approval
Total Pharmacy Services
Houma, LA 02/28/14 Compounded • Sanitary condi�ons • Microbial control SOPs •Personnel clothing • Environmental monitoring • Stability tes�ng • Conformance tes�ng • Iden�ty tes�ng • Drug approval
08/02/13 API • Computer access control • Method valida�on •Data integrity(audit trails, falsifica�on) • Component Tes�ng
Aar� Drugs 2 in Tarapur, India
07/30/13 API • Data Integrity(quality ac�vity records, recordkeeping, audit trails, computer access) • Devia�on/OOS inves�ga�ons
Wockhardt Aurangabad, India
07/18/13 Injectable, Oral Solid
• FDA inspector access • Data integrity(trial tes�ng,retes�ng) • Batch produc�on and control records • Lab control mechanisms • Toilet cleaning SOPs • Worker training
Fresenius Kabi Oncology
West Bengal, India
07/01/13 API • API Batch Combina�on • Data integrity(trialtes�ng, response to OOS, retes�ng, computer access) • FDA inspector access
I Shay Cosme�cs Gardena, CA 10/22/12 Topical • Microbial control SOPs • Specifica�on and testSOPs • Produc�on and process controls • Equipment cleaning • Stability tes�ng program • Component tes�ng
Stat Rx USA Jacksonville, FL
10/09/12 Oral Solid Returned drugs evalua�on • Stability tes�ng SOPs • Reserve samples of drug product
DPT Lakewood Lakewood, NJ
08/27/12 Topical • OOS inves�ga�ons • Microbial control SOPs
Infupharma Hollywood, FL
07/30/12 Compounded • Microbial control/SOPs • Process valida�on •Environmental monitoring • Employee training • Stability tes�ng • Data integrity(batch records) • Equipment SOPs • Complaint handling • Spec conformance • Produc�on records • Drug approval
06/20/12 API • Water system valida�on • Spec conformance •Equipment cleaning • Building maintenance • Devia�on/OOS inves�ga�ons • Method suitability tes�ng • Change control SOPs
Compania Internacional de Comercio
Mexico City, Mexico
06/13/12 Topical • Data integrity(reten�on) • Stability tes�ng •Employee training • Quality unit • Component tes�ng
B.M.P. Pharma Trading
Norderstedt, Germany
05/04/12 API • Area segrega�on
Selder S.A. de C.V.
Mexico City, Mexico
04/27/12 Oral Solid • Stability tes�ng • Method valida�on • QualitySOPs • Control records • In-process tes�ng • Drug Approval
The Impact of EU Directives and Guidelines on the Supply ChainJersey City, NJ (New York City Metro Area), USA – July 8-9, 2014A conference organised by the ECA Academy and the European QP Association
Highlights:Understand European GMPs
The European Pharmaceutical Legislation EU GMP Update Import/ Export EU PQR versus US APR The US Quality Unit versus the EU QP
Understand the Role of the QP Duties and Responsibilities The EU Discretion Paper and the Release of Batches Supply Chain and Supplier Qualifi cation
Plus:Clinical Trial Supplies: IMP Handling in Europe and the Role of the QP
The Role of PIC/S in a globalising World
The View of the FDA
SpeakersRichard M. Bonner Chairman of the ECA Foundation and the European QP Association
FDA Speaker(invited)
Dr Rainer GniblEU-GMP Inspectorate, Germany
Tor GråbergMedical Products Agency, Sweden
Dr Bernd RengerImmediate Past Chair of the European QP Association, Germany
Martine TratsaertJohnson & Johnson, Belgium
Mark Tucker, Ph.Dform. FDA Investigator and Compliance O� cer, USA
ECA
ACADEMY
European GMPs and the Role of the Qualified Person (QP)Qualified Person (QP)Qualified Person (QP)Qualified Person (QP)
European GMPs and the Role of the and the Role of the and the Role of the Qualified Person (QP)Qualified Person (QP)Qualified Person (QP)
Delegates’ Voices:“The chemistry between speakers and delegates was great.”
“Very interactive conference, very informative with real life examples.”
“Great broad coverage on topics relating to the QP.”
“I really enjoyed a conference that also addresses IMPs ! Thank you!”
Media Partners:
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FDA investigators are continuing to uncover serious data integrity issues at facilities in India, including repeat citations – highlighting the challenges regulators face in gettingcompanies to make changes in their quality culture.
Since the middle of 2013, seven Indian firms have received warning letters referencing the integrity of their records, procedures, and interactions with FDA investigators.
Those letters followed in the wake of an equal number of warnings issued from the beginning of 2012 to mid-2013 addressing integrity problems, three of which involved plants in India.
[Editor’s Note: For an in-depth analysis of the drug GMP warning letters issued by FDA from 2012 through mid-2013 that reference data integrity see IPQ “Monthly Update” July/Aug. 2013, pp. 2-8. The story focuses in particular on the issues that surfaced during that time frame at RPG, Fresenius Kabi, Wockhardt, and Ranbaxy. A listing of all 14 of the letters from 2012 through April 2014 that cite data integrity is provided below. The earlier IPQ coverage extended through the letter issued to Wockhardt in mid-July 2013. The Aarti Drugs letter in the listing was issued in late July 2013 and was not part of the earlier coverage.]
Large generic company Wockhardt, already on FDA’s data integrity watch list from a warning letter received at one of its plants in July, 2013, was delivered a second letter in November covering two other facilities that manufacture oral solid and injectable products.
Along with Wockhardt, four API manufacturers in India (Aarti Drugs, Posh Chemicals, Canton Labs and Smruthi Organics), one injectable firm (Agila Specialties) and one oral solid manufacturer (USV) also received letters that focused in part on integrity lapses.
In addition, data integrity issues were raised in 483s issued to Sun Pharma and Ranbaxy in December 2013 and January 2014, respectively. Both resulted in import alerts on products manufactured at the implicated facilities.
Problems were found at the Ranbaxy facility in spite of the company already being under a consent decree that was signed in 2012, arising from significant integrity issues uncovered at another two of its key India plants (ibid.). Sun announced in March that it was purchasing Ranbaxy from Daiichi Sankyo, and that fixing Ranbaxy’s compliance problems was a “top priority.” Sun’s own compliance
problems were not referenced in the announcement.
In late April, an Indian court temporarily halted Sun’s $3.2 billion purchase of Ranbaxy Laboratories until it decides on a petition for a probe into alleged insider trading.
FDA Warning Not Heeded by Wockhardt
Wockhardt’s problems detailed in the July 2013 warning letter were based on a six-day inspection of its Biotech Park facility in Waluj, India the previous March (ibid.). The letter provides eye-opening insights into the integrity lapses and efforts to cover them up that FDA has been finding in India.
Two days after the July letter was issued, agency investigators began simultaneous inspections of two of the company’s other plants in India – a second facility located in Waluj, and one in Chikalthana. Similar and repeat observations during the inspections led to a second warning letter to the firm five months later in December, addressing the findings at both facilities.
Observations cited in the December letter that were the same as those noted in July included: ● performing “trial” sample analysis ● QC laboratory computer instruments on which lab personnel could delete raw data files, and ● operations personnel performing manufacturing steps without a batch
FDA Data Integrity Findings Continue at Indian Firms, Highlighting Challenges in Changing a Facility’s Quality Culture
Warning Letters Since 2012 Specifically Citing Data Integrity Issues
record or a manufacturing form to document the results contemporaneously.
The repeat observations “indicate that your quality unit is not exercising its responsibilities and may not have the appropriate authority or ability to carry out its responsibilities,” according to the December letter. FDA was “particularly concerned” about the firm’s “inability to implement a robust and sustainable quality system.”
It “is apparent that Wockhardt is not implementing global and sustainable corrective actions,” the letter states. FDA “strongly” recommended that Wockhardt’s executive management “immediately undertake a comprehensive and global assessment” of its manufacturing operations “to ensure that your systems and processes, and ultimately, the drug products you manufacture, conform to FDA requirements for safety, efficacy, and quality.”
Using language identical to that in the July letter, the agency also “highly” recommended that Wockhardt “hire a third party auditor with experience in detecting data integrity problems to assist you with this evaluation and to assist with your overall compliance with CGMP.” The letter adds that it is the firm’s responsibility to ensure that data generated during operations is “accurate” and that the results reported are “a true representation” of the quality of its drug products.
In responding to the letter, FDA’s Office of Manufacturing and Product Quality (OMPQ) Director Steve Lynn asked Wockhardt to “provide a list of all the batches of drug products shipped to the U.S. market that relied upon missing, inaccurate, or unreliable test data.”
Just prior to the December letter, FDA issued an import alert restricting entry into the US of human drug products manufactured at the two plants.
After the letter was issued, a second import alert, described as “detention without physical examination” of veterinary drugs from the plants, was announced. While the company had reportedly sold its animal health division in 2009 to the French veterinary care company Vétoquinol, Wockhardt may have been manufacturing veterinary drugs on a contract basis in a way that was not apparent earlier to FDA.
State FDA in India FDA Weighs In
In late March, the Food and Drug Administration for the Indian state Maharashtra issued “show cause notices” to the Wockhardt plants that had received the FDA warning letters, according to the Indian newspaper DNA.
DNA was reportedly informed by a source from Wockhardt
that Maharashtra FDA officials sought an explanation as to why GMPs are not being followed.
The Indian news source reported that last December the Indian state agency instituted a three-member special investigation team (SIT) comprising drug inspectors from Ahmednagar, Solapur and Mumbai to inspect the three pharma plants.
The inspection report, which was obtained by DNA, cited significant violations of GMPs and general sanitation expectations, including: ● biomedical waste dumped openly ● up to 114 rusted drums containing glycerine – used inmaking injections – lying unused for months ● a proliferation of insects and rodent excreta, and ● used gloves and medicine packs lying in the open.
An official from the inspecting team explained to DNA that empty trial tablet packs, which are produced to check packaging norms, were dumped in the open, and could have easily been stolen or illegally recycled for use with counterfeit medicines.
He also noted that 5,000 vials of agar gel, which is used as culture medium for injectable products, were lying in the open – presenting an ideal breeding ground for the uncontrolledgrowth of microorganisms, threatening contamination of the atmosphere.
State FDA commissioner Mahesh Zagade confirmed in late March in an interview with DNA that the “show cause notices” were issued and that Wockhardt has been asked to respond.
According to the DNA report, Zagade said that if drug inspectors find that the plants do not step up their compliance level, suspension or cancellation of manufacturing license may be initiated.
Since 40% of the medicines being produced in Indian plants are exported abroad, India needs to be wary of faulty practices to ensure its export market, he emphasized.
On April 22, Wockhardt announced a further suspension imposed by Indian regulators.
The firm said that the “State Drug Controller in Himachal Pradesh has suspended the manufacture, sale or distribution” of its fixed-dose combo drug made up of dicyclomine HCl 10 mg, tramadol HCl 50 mg and acetaminophen 325 mg. Wockhardt said the drug accounted for 3% of its sales last year and that is was appealing the suspension.
The suspension resulted from a tip to the Indian agency that some of the ingredients the company used to make the painkiller had been banned by the Indian government,
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Himachal Pradesh state drug regulator Navneet Marwah told Reuters.
He explained that the action was taken after receiving complaints from consumers, adding that his office has reported the problem to the federal authorities and that the ban would remain in place until action was taken at that level.
The suspension was revoked on April 26 after the federal agency investigated and said it found no problems with the products’ safety and efficacy, a state drug regulator told Reuters.
Ranbaxy Had Similar Issues
Data integrity issues reported by FDA in the Wockhardt warning letters were similar to those that led to the Ranbaxy consent decree in January 2012 (see IPQ “Monthly Update” February 2012, pp. 23-30).
The decree stemmed from investigations by FDA beginning in 2008 that revealed numerous problems with Ranbaxy’s drug manufacturing and testing at facilities in both India and the US, and data integrity problems at its India operations, including backdating of tests and submitting test data for which no test samples existed (see IPQ May/June 2009).
In May 2013, the firm pleaded guilty to three felony counts of violating federal drug safety laws and four of making false statements to FDA.
The issues at Ranbaxy continued to garner media attention as more information surfaced from former Ranbaxy employee whistleblower Dinesh Thakur, which outlined a culture of fraud and corruption (see IPQ “Monthly Update” July/Aug. 2013, pp. 2-8.)
In a statement released after the guilty plea was entered, Ranbaxy noted that the settlement involved “conduct that occurred several years ago.” Ironically, Ranbaxy CEO Arun Sawhney said in the statement that “today’s announcement marks the resolution of this past issue.”
Ranbaxy’s Past Is Prologue
An FDA inspection at a Ranbaxy plant just eight months after the guilty plea indicated that the company’s problems had not been resolved.
In January 2014, FDA inspectors visited a Ranbaxy facility in Toansa, in a rural area north of New Delhi, and found data integrity and GMP issues similar to those uncovered in the previous inspections of Ranbaxy sites that led to the warning letter and consent decree.
Investigators discovered workers running analytical tests repeatedly until they got the desired results, computer systems that allow deletion of raw data by operators, and back-dating of forms – including those specifically used to comply with the terms of the firm’s consent decree – according to the FDA 483 issued after the inspection.
In addition to the data integrity issues, the investigators also found GMP problems in the laboratory, including unusable equipment, open windows that could not be closed, flies “too numerous to count,” and a defective refrigerator containing a pool of water where working standard sample containers were stored.
Investigators emphasized that the same lab observations were previously noted and discussed with company management during an inspection close-out meeting in December 2012.
Shortly after the inspection, FDA placed an import alert on the APIs made at the Toansa plant. The agency had already restricted imports from three other Ranbaxy facilities in India, including those in Paonta Sahib, Dewas and Mohali, resulting from previous poor inspections.
Ranbaxy voluntarily suspended all shipments of APIs from Toansa and a second Indian plant in Dewas after the FDA ban, Ranbaxy’s parent company, Tokyo-based Daiichi Sankyo, said in a Feb. 25 statement. Ranbaxy is continuing to make finished products for non-U.S. markets using API inventory from Toansa and Dewas and from external sources.
In late March, Indian authorities withdrew the Toansa site’s “written confirmation” – effectively suspending the export of products, as the confirmation must accompany APIs shipped to foreign countries.
The announcement came only days after Indian-based Sun Pharma announced it would buy Ranbaxy in a $3.2 billion all-stock deal with Daiichi Sankyo. The combined entity will be the world’s fifth largest generics maker with $4.2 billion in revenue, with the U.S. accounting for $2.2 billion.
EMA said in early April that a team of inspectors from Germany, the U.K., Ireland, Switzerland, and Australia performed an “unannounced” inspection at the Toansa facility following the FDA import ban, and found issues similar to those found by FDA. EMA is planning an inspection of the Ranbaxy Dewas plant in June. The European agency said it will not permit any imports from the two facilities until it has confirmed that the problems have been fixed.
Both Ranbaxy and Sun recently announced product recalls, both for oral solid products.
In mid-March, Sun initiated a voluntary recall of nearly
3,000 bottles of metformin hydrochloride extended release tablets after a customer complained of the presence of some gabapentin tablets, a drug used to treat seizures, in a bottle.
In late April, Ranbaxy announced a Class II recall that it had begun in February of nearly 30,000 packs of an allergy-relief medicine containing loratadine and pseudoephedrine sulphate extended release tablets for packaging defects. The product was manufactured by the firm’s Ohm Labs plant in New Jersey, which is the company’s only facility currently making generics for the U.S.
Imports Also Banned from Sun Pharma Plant
Ranbaxy’s purchaser Sun Pharma also found itself in regulatory trouble after a late-2013 FDA inspection, which resulted in an import alert in mid-March, 2014.
Notably, the same FDA investigators who inspected Ranbaxy in January had previously inspected Sun’s cephalosporin facility located at Karkhadi, Gujarat in India in November – Peter Baker and Dipesh Shah, both consumer safety officers based in FDA’s India office. The plant is one of 25 that Sun owns, and accounts for less than 1% of the company’s sales.
The form 483 issued by the investigators at the conclusion of the inspection was obtained by Economic Times of India (ET), which published many of the observations.
“Drug products failing to meet established specifications and quality control criteria are not rejected,” the 483 noted. Investigators “identified multiple torn/partially destroyed raw data CGMP manufacturing and quality records.”
Their review of the records, the 483 reports, “identified the practice of maintaining duplicate versions of cGMP raw data records. Undesirable data was found to be changed in the official versions in order to meet specifications.”
The 483 also reported observations of poor housekeeping and unsanitary conditions, characterizing the toilet facilities as in a state of “total disrepair.”
“The two urinals present in the washing and toilet facility provided for quality control laboratory male employees were found to drain directly onto the floor. Urine was found to be collected in and around an open drain. A strong smell of urine was observed throughout your firm’s quality control environment,” the 483 states.
Investigators also noted a garbage dump in the perimeter of the manufacturing area and various forms of infestation. “Buildings used in the manufacture, processing, packing or holding of drug products are not free of infestation by
rodents, birds, insects and other vermin.”
Ironically, two years earlier, Sun Pharma had been asked by FDA to step in to fill a shortage when Johnson & Johnson was no longer able to supply its injectable cancer drug Doxil to the market due to compliance problems at its Doxil contractor, Bedford, Ohio-based Ben Venue.
Compliance problems uncovered during mid-2011 inspections by FDA and EMA at the Ben Venue facility resulted in the site halting manufacturing, and eventually led to critical shortages of the drug (see IPQ “Monthly Update” November 2011, pp. 48-50). Injectable Doxil is used in multiple treatment regimens, including treatment of ovarian cancer after failure of platinum-based chemotherapy. The drug is also indicated for use in AIDS-related Kaposi’s sarcoma and multiple myeloma.
In response to the shortage, FDA allowed the importation of Lipodox, an injectable Doxil substitute manufactured by Sun that had not been approved in the U.S. (see IPQ “Monthly Update” March 2012 pp. 11-13). In 2013, FDA approved a generic version of Sun’s drug for the U.S. market that further helped ease the shortage.
Temporary importation of unapproved foreign drugs is considered in rare cases when there is a shortage of an approved drug that is critical to patients and the shortage cannot be resolved in a timely fashion with FDA-approved drugs.
In 2009, FDA ordered manufacturing to be halted at Sun’s Detroit-based unit after a string of recalls over manufacturing defects. Three years later, the FDA cleared the subsidiary to resume operations with two products.
Other Indian Firms Banned
In 2013, FDA banned about 20 plants in India from exporting drugs to the U.S. and warned several others.
The most recent import alert was placed on Canadian-based Apotex’ plant in Bangalore in early April, due to significant GMP deviations.
The alert covers the company’s drugs and antibiotics, with the exception of riluzole, used in the treatment of amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.
Apotex received a warning letter in early 2013 for issues discovered during an August 2012 inspection of its Richmond Hill, Ontario, Canada facility. The letter pointed to GMP concerns regarding: ● microbial control SOPs ● OOS investigations ● process validation ● laboratory records ● environmental monitoring, and ● CAPA.
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An import alert was also placed on APIs coming from Canton Labs’ facility in Vadodara, India after its receipt of a warning letter at the end of February (see story on p. 3).
Topping the warning letter was the finding during an inspection a year earlier that Canton was reporting on its CoAs that batches were meeting microbial and metal impurities limits without actually doing the testing or having any supporting data.
Data Integrity Warning Letters Examined
At a PharmaLink conference in March in Cincinnati, Ohio, co-sponsored by FDA and Xavier University, National Expert Investigator Rebeca Rodriguez provided her perspective on the problems the agency is seeing with data integrity in the context of warning letters issued to foreign firms in 2013-2014 (see box below for Rodriguez’ complete remarks on this topic).
Although data integrity issues are more frequently discovered in certain countries, Rodriguez emphasized that FDA is not “targeting any particular country.”
The recurrence of warning letters citing data integrity problems to firms in particular countries may be reflective of a number of factors, she said, including: ● “regulatory maturity” ● experience of the investigator, and ● location of the firm within a country.
The regulatory maturity of both the country regulators and the inspected firms is an important factor, Rodriguez commented. She explained that regulatory maturity “comes from experience and knowledge of what things can happen.”
“It is not that people don’t know or people are stupid – it is regulatory maturity. We learn from mistakes. And we learn from things that can happen and from risks that we didn’t see before.”
Regulatory maturity can also manifest itself in terms of the investigator performing the inspection, with more experienced investigators better able to uncover problems.
“I know for a fact,” the FDA expert said, “that some of the [agency] people involved in the data integrity warning letters are people who have a lot of experience, because they have worked with these systems themselves. They know the lab systems and how to work with them.”
Rodriguez also pointed to the geographical location of a firm as an important factor in being able to attract and retain the expertise it needs to become and remain compliant.
“I have seen companies that have very knowledgeable people, but their area of expertise is maybe for the same processes, but for food establishments, not for drugs. I have seen people who mean well. They were knowledgeable of the processes, but they were not knowledgeable of the drug regulations.”
“It is not only the country, but even within a city,” the expert investigator commented. One company she is familiar with face problems in getting people with “the right expertise” due to its location outside of an area where people wanted to live. “They wanted to live near the nice city, not an hour away. I have seen this with some companies that are having trouble hiring the right expertise because their sites are not located where people want to be.”
FDA’S RODRIGUEZ ON DATA INTEGRITY IN FOREIGN WARNING LETTERS
At a Xavier University/FDA PharmaLink conference in March, FDA National Expert Investigator Rebeca Ro-driguez explored the data integrity issues the agency has communicated to firms through warning letters during 2013 and 2014. She specifically addressed: ● ignoring bad lab data ● lab documentation and audit trails ● computer system security ● the use of post-it notes and other uncontrolled documents ● signing off on steps before they have taken place ● blending API batches, and ● the impact on supplier firms.
I looked at warning letters that were issued to foreign and domestic firms in 2013 and 2014. I particularly looked at four warning letters that were issued to drug manufacturers – including one API manufacturer, and 13 foreign firms. Some of these warning letters were issued to multiple facilities of the same company. Some of these warning letters were also issued for OTC manufacturers, re-packers, re-labelers, contract labs, etc. But the bulk were mostly to API and finished drug product manufacturers.
When I was looking at those warning letters, what really stood were data integrity observations – data integrity issues with foreign establishments. I don’t know how familiar you are with the issues, but it has been in the news…
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We are really not targeting any particular country. But the data integrity problems may reflect on several factors regarding regulatory maturity of the companies and the country…. There are a number of things that may be playing into this recurrence of warning letters to particular countries.
Part of those warning letters were also related to the integrity of data that is coming from computer systems, which is also part of data integrity. That was the point in showing warning letters relating computer systems to the integrity issues. And there also was a failure to review and investigate production and QC laboratory deviations. Those are the three things that stood out to me in those warning letters.
The data integrity issues were mostly related to HPLC processing methods – for example, people running multiple runs of the same samples and changing integration parameters until they got the results they expected or wanted. That is obviously not acceptable. That is basically testing into compliance. For whatever reason – I am not saying it was intentional, I am not going there – it was happening.
Another issue that was found during these inspections was the documentation trail of the computer systems, of the chromatographic systems, was disabled. The audit trail basically tells you every time someone performs a critical operation with a signature – that the system documents that step, and that that action was taken. That trail was disabled. They were changing data and changing parameters. Whatever the functions that the audit trail was supposed to follow were not being documented. The absence of that audit trail was enabling people to delete data and change operation parameters, integration parameters, and that kind of stuff. They used the same password and username. That is a clear no-no. But we still find these things. I, myself, have found companies that are still doing this.
Another issue that the investigators found was that the system did not protect the data. It was possible to access the system and make changes or deletions to the system. These are just similar iterations of the same issue – the failure to implement access controls to the system.
Excel spreadsheets were also mentioned. Calculations in the spreadsheets were not protected. People could make changes to the formulas that were in the spreadsheets. This is pretty much the same stuff. These are just some of the issues that were cited related to computer systems.
There were also less complex issues. Speaking of complexity or lack of complexity, in this particular case, people were using post-it notes or small pieces of paper to write stuff, and then they were transferring that to worksheets or formal documentation. That kind of practice lends itself to people documenting the data to meet whatever expectations they have. So that is completely unacceptable.
And also, people were performing multiple runs of the same samples, and calling them different names such as trials or demos, until they got the ones that were acceptable. Out-of-specification (OOS) results were ignored and not investigated – they were accepting only the good results.
I thought this one was really interesting. In this case, the reason for the continuous testing and re-testing was that the company was having API batches that failed. They were blending the bad batches with the good batches and they were running them again, so then they got a good result. The blending of a bad batch and a good batch is a GMP violation in itself. Then they covered that up in the re-testing practice.
In this particular case, the managers of the company claimed in their response to the 483 that they didn’t know why operators were doing that. Personally, I have a hard time believing that. I don’t have any stake in the company or that batch. I am not getting the money for that batch. So I don’t know how this practice was not being encouraged by management. I just really wonder when I see stuff like this.
Other issues that they found were that people were pre-documenting operations. If they were going to perform a step, they would fill in the data before they performed a step. So that was a little bit of foreseeing an event or something. This happened not only in lab operations, it was happening in manufacturing operations as well – they were not documenting operations as they were performed.
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Data Integrity Findings Impact Shareholder Value
Following Rodriguez to the podium at the Xavier/FDA conference in March, MHRA GMDP Inspections Group Manager Mark Birse provided an analysis of the impact of the data integrity observations on the market value of a firm.
Birse provided a case study that involved inspections conducted simultaneously by FDA and MHRA during which many of the data integrity deficiencies Rodriguez pointed out in her talk were uncovered. While neither mentioned the firm’s name, Wockhardt clearly fits the profile.
The UK official noted that the share price for the firm involved had quadrupled during 2012. However, as inspections revealed deficiencies that resulted in FDA import alerts and EU statements of non-compliance (SNC), the value of the company declined rapidly (see box on following page).
The three inspections conducted are represented in the figure by red circles. During first inspection, MHRA was “on site at exactly the same time as FDA,” Birse noted, and uncovered many of the same integrity issues.
The first stock price drop occurred when FDA issued an import alert, followed by a smaller drop after EU issued an SNC.
A second MHRA inspection of a different site coincided with the issuance of an FDA warning letter to the company that resulted from the first inspection. During the second inspection, the company issued a statement to the press that the inspection “was not going well,” Birse commented, at which point the stock price “hit rock bottom.”
After the stock drop, the firm issued another statement to the press “to try and put a positive spin on things,” at which point the price went up slightly. “But then in the EU we issued a statement of non-compliance for ‘site two’ and a statement of non-compliance for ‘site three,’ which we had
inspected,” he explained.
“All in all, all of the good work that that company had previously been doing building up share prices for investors was just destroyed,” Birse said.
“Just imagine how much stock value was being lost during that time. Imagine if a small slice of that had been taken off and been spent on quality – actually doing the right thing. They would not be in this position now if they had really thought about it.”
MHRA Data Integrity Expectations Outlined
Birse went on to discuss his agency’s expectations for a company’s review of data integrity during its internal audits. The expectations were published on MHRA’s website in December (see box below).
Those are the data integrity issues that were reported in multiple warning letters. And it was to one particular country. When I look at this, I wonder what the outcome of this is, because some of these firms were placed on import detention. Basically, they can’t sell product to the U.S., though in some cases the FDA had to allow some things into the U.S. for very specific reasons.
But what does a company do when their supplier of a critical API cannot supply because they have been placed on import detention? What does a U.S. manufacturer do about that? It is a huge problem. Could that U.S. manufacturer have prevented these problems to some extent by doing their homework and qualifying their supplier? That is a question. I am not concluding anything. These data integrity issues are not always easy to find. On the other hand, in these particular cases, they seemed to be pretty extensive practices. There were things that the investigators readily found.
MHRA Expectations for Data Integrity Self Auditing
The following expectations regarding self in-spections by pharma firms were announced by the UK’s MHRA in December, 2013:
● The MHRA is setting an expectation that pharmaceuti-cal manufacturers, importers and contract laboratories, as part of their self-inspection program, must review the effectiveness of their governance systems to ensure data integrity and traceability.
● This aspect will be covered during inspections from thestart of 2014, when reviewing the adequacy of self in-spection programs in accordance with Chapter 9 of EU GMP.
● It is also expected that in addition to having their owngovernance systems, companies outsourcing activities should verify the adequacy of comparable systems at the contract acceptor.
● MHRA invites companies that identify data integrityissues to contact them by email at: [email protected]
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“We thought long and hard about what a company is going to do” if it finds data integrity problems, Birse commented. “Are they going to come to us? We do invite you to come and tell us if you find data integrity issues.”
He emphasized the double-edged sword nature of the endeavor. “If you find a data integrity issue, we want you to come and discuss it with us. Now it may be that it is so serious that we still end up having to take regulatory action. But at least we can sit down and have a sensible discussion.”
What the agency does not want to have happen is firms finding data integrity issues and “burying” them. “We really
Share Price During 2012
Share Price During 2013U S FD A Im port A le rt S ite 1 E U S N C S ite 1
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Cost of Non-Compliance to WockhardtThe following charts depict the impact on Wockhardt share price in the wake of the adverse inspection findings by FDA and MHRA, which included the lack of data integrity. The three red circles in the second chart represent the MHRA and FDA inspections.
need to engage and have sensible discussions if you do find those issues so we can work through them together.”
Detecting and Preventing Data Integrity Problems
At an ICH Q7 training workshop cosponsored by PIC/S and PDA in February 2014 in Bethesda, Maryland, FDA Division of International Drug Quality Director Carmelo Rosa reviewed aspects of data generation and traceability, the systems used to generate it, and the controls that should be in place to ensure its integrity.
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He listed eight questions firms should ask when examining data and the systems producing it (see box below).
“If the data is complete,...if the data is reliable and consistent and accurate, then you have good data integrity,” he said. “That is what we expect from firms.”
On the other hand, a firm’s inability to detect and prevent poor data integrity practices “raises serious concerns about the lack of a quality system’s effectiveness and the decisions made using that data,” Rosa emphasized.
Regarding active pharmaceutical ingredient manufacturing operations, the agency director pointed out that production needs to have sufficient control to prevent unauthorized changes to data as clearly stated in Q7. There should be controls to prevent omissions in the data to avoid systems being turned off and data not captured. This is a problem area FDA is seeing “more and more.”
Finding Integrity Problems is Difficult
Rosa stressed that it can be difficult for FDA investigators and inspectors from other regulatory agencies to find data integrity problems. “You can’t just go into a facility and have data integrity just jump out at you.”
Investigators may only have four or five days to perform an inspection, and “finding the evidence of wrongdoing and documenting it is a very tough job,” he commented. “I haveall the respect in the world for the investigators. I have been there. I have done many inspections. I have the highest
Keys to Prevent & Detect Data IntegrityAt the ICH Q7 training workshop, FDA’s Rosa presented the following list of questions to ask when examining data and the systems used to assure its integrity:
● Is the data reliable, trustworthy and verifiable?
● Was the data generated following GMPs ?
● Is the data traceable and/or referenced to original raw data and reviewed by a reliable quality structure ?
● Are the appropriate controls in place to ensure that all data is reported?
● How long in a process can an employee go w/o direct oversight?
● How do you know all the data is available?
● Do you have mechanisms to ensure the data is au-thentic, retrievable?
● Where critical data are being entered manually, is there an additional check on the accuracy of the entry? This can be done by a second operator or by the system itself.
respect for them because of the difficulties of identifying these types of problems.”
To be effective, investigators need to understand the systems they are evaluating and how to “look at the process from a different perspective.”
Rosa declined to share how agency investigators are trained to find integrity lapses. “I am not going to tell you is our bag of tricks,” he said. “I can’t.”
One reason he chose not to share the information is because “many firms are not using that information to get better at what they do. Unfortunately, some of them are using that information to cut corners and get more sophisticated” in how to hide data integrity issues.
Rosa commented that he sees all foreign GMP inspection reports, and has seen “how sophisticated some companies are becoming in deceiving and engaging in these types of bad practices.”
Establish Audit Trails
Rosa emphasized the importance of recording any changes made and of having an audit trail that traces back to original raw data.
He noted that the agency has seen “many” quality units in which an analytical or quality package is received, and those responsible for approving it “review it, sign off on it, but don’t spend time going into the system to see the audit trail. They don’t go into the system to see if there were failing results that were not reported. They don’t take the time to look at and challenge the data that they are reviewing. That, of course, is a gap in that operation.”
Rosa pointed to the importance of the quality system reviewing data to help prevent and detect data integrity issues.
“Is the reference to the raw data and the review done by a reliable quality structure?” he asked. “Why is this important? If you have wrongdoings on the floor, and you have a broken quality system, the rest doesn’t matter...How can you rely on the quality system when they are aware of and are not actually responding or doing the right things to bring that operation under a state of compliance?”
All data must be reported, not just selective data that supports a desired outcome. Computer files that are “discarded or ignored” should be easily retrievable.
Also important for industry to consider, Rosa commented, is the length of time an employee can go unsupervised. “How much can an employee, an analyst or operator do on his own without being supervised or without somebody having direct oversight and challenging the operation?”
Challenging Authority Problematic
Rosa explained that there are countries and places where “it is almost seen as a sin to challenge an authority – to challenge
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higher level management.”
He commented that some cultures instill a sense of respect for elders and people in positions of authority at a very young age, and breaking away from that is difficult.
“When I look at my dad, I still bow my head,” he said. “That is the sense of respect that we had growing up for the people who had authority over us. And that is no different than what we see in some firms and some cultures – there is just such high respect for that authority that, God forbid, we try to tell them, ‘this is wrong, I can’t do it.’”
In such cultures, it is especially important “to make sure that the entire operation and culture understand the expectations of regulators, but also of what good GMPs mean.”
“Who? When? What? And how is the data collected? How is the data processed? Is the data reviewed and is the data reported? Who does it? When was it reported? What data are we looking at? And how is it reported? Just basic questions to keep in mind.”
Capitol Hill Briefed on Problems in India
“Searching for Safety,” an organization that tracks and reports on counterfeit and substandard medicines, sponsored a “briefing” in late February in a Congressional meeting room on “FDA, India and substandard drugs.”
About four dozen congressional staff, FDA, White House and State Department representatives attended the briefing, Bloomberg reported.
Presenters at the briefing and the topics they discussed were:
● Ranbaxy whistleblower Thakur outlined problems with substandard generic drugs and manufacturing processes in India, their causes, and what could be done to solve them (see box below).
● Amir Attaran, a Professor of Law and Medicine at the University of Ottawa, discussed the risks of substandard and falsified medicines, especially those made in India. He cited “obsolete” Indian laws and a “lack of oversight” by India’s FDA as primary reasons for concern about the quality of drugs made there.
● Harry Lever, a senior cardiologist at the Cleveland Clinic, discussed the problems resulting from his increasing encounters with inferior quality medicines and how clinical outcomes from generic medicines made abroad generally compare unfavorably with those made in the U.S. He presented anecdotal evidence showing that his patients taking the cardiac drug metoprolol succinate experienced adverse symptoms that “seemed to improve” when they were switched from an Indian-made version of the drug to a U.S.-made product.
● Preston Mason, a member of the Cardiovascular
Division at Brigham and Women’s Hospital and Harvard Medical School, presented his extensive research into poor quality atorvastatin (generic Lipitor), which he maintained shows that “generic Lipitor samples from overseas had elevated and alarming levels of impurities” compared to those produced in the U.S.
Hamburg Proposes India Observing FDA Inspections
A week before the late-February briefing, FDA Commissioner Margaret Hamburg traveled to India to meet with government officials on quality and other regulatory topics.
Hamburg’s visit included the signing of a “Statement of Intention” to clarify the points on which both countries will cooperate, such as: ● sharing of CGMP compliance and facility information, ● India investigators observing FDA inspections, and ● enhancing communication and public meeting collaboration.
Thakur, Attaran and American Enterprise Institute Adjunct Scholar Roger Bates, who organized the late-February briefing, commented on Indian agency officials observing FDA inspections in an op-ed piece in Forbes in late March.
Allowing the officials access to FDA inspection methods “may inadvertently make it easier for Indian companies to cheat,” they wrote. Congress should impose “severe penalties in the form of trade barriers on any country that repeatedly exports poor quality medicine to America,” the authors suggested.
FDA’s recent enforcement actions involving data integrity received attention at a session of the PDA annual meeting in San Antonio, Texas in April.
The session began with Sanofi Global Quality VP Edwin Ri-vera-Martinez, a former FDA compliance official and ICH Q7 expert working group member, highlighting some of the recent enforcement trends and setting up the data integri-ty discussions that followed. CDER Senior Policy Advisor Karen Takahashi, who serves as a point person on integrity issues at the drug compliance office, provided her office’s current thinking on data integrity and what FDA is look-ingfor and finding during its inspections (see IPQ “Monthly Update,” May 2012, pp 11-15 for the full text of a similar presentation by Takahashi at the 2012 University of Geor-gia/FDA GMP conference).
A revealing presentation followed by Katherine Eban, a journalist well known for her book on drug counterfeiting, “Dangerous Doses,” and a recent article, “Dirty Medicine,” which probes into the Ranbaxy case and Thakur’s role as whistleblower (see IPQ “Monthly Update,” July/August 2013, pp 2-8). Rounding out the session was Interpro QRA Senior Consultant Douglas Campbell, a former CDER com-pliance official with expertise in the integrity arena.
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RANBAXY WHISTLEBLOWER DINESH THAKUR ON PROBLEMS IN INDIA’S GENERIC DRUG INDUSTRY AND PROPOSED SOLUTIONS
The following is excerpted from a statement by Ranbaxy whistleblower Dinesh Thakur at a briefing on “FDA, India and Substandard Drugs,” held on Capitol Hill in late February 26, 2014. Thakur outlined the problems with substandard generic drugs and manufacturing processes in India, their causes, and what can be done to solve them.
My name is Dinesh Thakur. I am the whistleblower in the case against Ranbaxy Laboratories, which was unsealed last May where the company pleaded guilty to seven counts of felony in a US court and agreed to pay $500 million in penalties. I am here today to speak about the risk we face as to public health with adulterated drugs resulting from a globalized supply chain and what we are asking the US Congress to do to address this risk….
We have made tremendous progress in our understanding and oversight of the global supply chain that provides life-saving medicines to patients in the US, [including through provisions in FDASIA, (see IPQ September 29, 2013) and the “Drug Quality and Security Act” (see IPQ January 23, 2014).]
My case against Ranbaxy in India and what happened with heparin in China demonstrate that unscrupulous actors in the global supply chain take advantage of gaps in our regulation for financial gain. Economically driven adulteration has become a new category of fraud in the pharmaceutical industry….
While the U.S. FDA is making every effort to address this area of risk, based on my past experience, incentives need to be aligned for pharmaceutical companies located overseas to play by our rules….
In order for the efforts made by the FDA to produce the desired results, we need an able and willing partner in the overseas regulators. Unfortunately, their objectives are more aligned with promoting commercial interests of their industry than focusing on public health. I wish regulators overseas were as capable and competent as the US FDA; unfortunately, they are not. In fact, the Parliament of India has called the Indian regulator incompetent and corrupt.
As much as the FDA expands its footprint in countries like India and China, it cannot replace the role of a national regulator whose job ought to be to protect public health by guaranteeing good quality medicines for its people. Data confirm that one in five medicines that are manufactured and distributed in India are spurious. Recent news reports say that antibiotics administered intravenously to infants in the state of Kashmir did not have any active ingredient in it, leading to deaths of several hundred children.
Clearly, we need a competent and effective national regulator in countries which provide medicines for the US marketplace to work collaboratively with ours. The FDA can educate, but it cannot enforce local standards, which vary widely among countries that supply our medicines.
I am here today to ask you to consider three proposals that I think will help alleviate this problem to a large extent.
1. Incentivize the countries that supply our medicines to upgrade their skills, comply with our quality standards andimprove public health for their own citizens. The US Congress will have to take a carrot and a stick approach. As much as it wants to educate and train foreign regulators, please also consider punitive action against repeat offenders.
2. Make the reporting of drug substitution (substituting a brand drug for a generic due to lack of effect) mandatory. Wejust do not have enough data to really understand what impact generic substitutions have on our public health. While lack of effect cases are reported to the FDA Medwatch, we need additional data to better understand whether the lack of effect was due to a generic substitution.
3. Make the pharmaceutical industry monitor its supply chain for economically driven adulteration, especially fromsourcing ingredients to manufacturing the product. We need to complement the existing track and trace legislation to make sure that the other half of the supply chain is also monitored continuously for risks from global sourcing and manufacturing. After all, what good is it to track and trace a product that is adulterated in the first place?
There are, unfortunately, no quick fixes in the long road towards drug safety. However, if we work together and apply the right mix of force, incentives and education, I am confident we can foster a much safer and more dependable generic drug supply chain.
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Inadequate testing of incoming components is a leading problem area being cited by FDA on finished drug product GMP warning letters and is particularly prevalent in the expanding number of those addressing compliance at topical manufacturers worldwide.
FDA is expressing concern that each component is not being tested by the dosage manufacturer for conformity with all of its specifications and/or that specific identification tests are not being conducted on components that have been accepted based on the supplier’s certificate of analysis (CoA), as required by CFR 211.84.
IPQ’s analysis of drug product GMP warning letters issued from 2012 through the first quarter of 2014 shows that over one in three of those addressing finished product manufacturing (20 of 56) have highlighted non-compliance with 211.84. Among warning letters addressing topical manufacturing, the percentage soars to three in four (16 of 21).
Topical manufacturing, meanwhile, emerges as the leading target of drug GMP warning letters during the past two years.
The 21 topical warning letters issued since the beginning of 2012 represent 37% of those addressing dosage form manufacturing – exceeding the number issued to injectable manufacturers (17) and oral dosage firms (13). Topical letters also outpaced those addressing API manufacturing (15).
The finding is dramatic in that in the five years prior to 2012, topical firms received only about one third as many letters as oral manufacturers – which led the warning letter totals during that timeframe – and significantly fewer than either injectable or API operations.
It is clear that topical OTC manufacturing is getting more attention as FDA’s GMP enforcement efforts intensify in the global arena. Also clear is the concern around how topical firms are handling their component evaluation process and that the agency will not be tolerant when the requirements in this area are not being met.
OTC GMP and Monograph Problems Intersect
80% (17 of 21) of the topical operations addressed in the 2012-2014 warning letter cohort make OTC products. Most of the OTC topical letters link GMP non-compliance with the finding of products that are not in conformance with OTC monographs for labeling and/or ingredients, effectively
making them unapproved new drugs.
Without the driver from the new drug application approval process, OTC manufacturing has not received as much inspection attention from FDA – particularly overseas where the majority of the topical warning letter recipients are located. In this context, it is not surprising that when the agency does visit these firms, it uncovers compliance problems that reach actionable significance.
From 2012 to Q1 2014, eight warning letters were issued addressing OTC oral dosage form manufacturing – a few of the facilities were also making prescription products. Three of these highlighted component testing among the GMP problem areas. Adding in topicals, 24 of the 56 warning letters issued to dosage manufacturers during this timeframe involved OTCs.
Prompting FDA to get to more of the OTC manufacturers is its ongoing effort to get non-monograph-compliant/unapproved drugs off the market – an effort that has been expanding abroad, as the warning letter data underscores. CDER’s compliance office has indicated that unapproved drugs will remain a priority in 2014 (see IPQ “Monthly Update” January 2014, pp. 13-20).
Half of the OTC-oriented warning letters in the 2012-14 cohort (12 of 24) also reference compliance with the formu-lation and/or labeling requirements of the monograph system.
Another salient aspect of these OTC warning letters is the number of repeat observations they contain. And the problems referenced are not in the somewhat more subjective realm of how well deviations are investigated, but address basic direct threats to the quality and safety of the products.
Manufacturers that are not constrained by the drug approval rules also appear immune to the GMP dictates, and they do not readily change their behavior, the warning letter data indicates. Clearly one inspection visit is not enough in many cases to have an impact – a reason why this arena is a resource intensive one for FDA.
The CGMP/drug approval nexus of problems takes another form in the bolus of warning letters that have gone out to injectable compounders in the first quarter of 2014. Nine of the 11 drug GMP warnings issued during the quarter went to compounders
Component Testing Gains Prominence in Drug Product GMP Warning Letters as FDA Focus Intensifies on OTC Topicals and Upstream Supply Chain
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(see story p. 36).
The letters followed in the wake of the agency’s 2013 inspection blitz of high-volume sterile pharmacy compounding operations nationwide and legislative empowerment through the Drug Quality and Safety Act (DQSA), signed into law in November.
The compounding provisions of DQSA clarified FDA’s ability to take enforcement action against the large-scale compounders on both CGMP and drug approval non-compliance grounds (see IPQ “Monthly Update” Nov.,/Dec. 2013, pp. 28-30). They also define a new category of compounder called “outsourcer,” which will give compounders that qualify relief from the drug approval and labeling rules. However, they will have to meet relevant drug GMP requirements to qualify.
Incoming Materials Need Policing
The problem of inadequate component testing was addressed in 10 of 11 warning letters to topical manufacturing facilities outside the US, and in six of seven to those issued domestically. The other four letters referencing 211.84 went to oral product manufacturers (including the one letter addressing veterinary drug compliance).
Given the broad universe of GMPs and that ingredient testing is part of the materials handling system, which is not automatically covered in domestic inspections, the frequency of its appearance on the warning letters is significant.
The prevalence of the concern with excipient and API testing on the foreign finished product warning letters reflects, in part, the broader review that investigators do when applying FDA’s system-based inspection approach overseas. Foreign inspections generally cover all six systems.
A domestic inspection, on the other hand, may only focus on the quality system and one of the other five, and not necessarily the materials handling system addressed by 211.84. The not-infrequent appearance of the component testing cite on the domestic warnings speaks to FDA’s view of its importance, accordingly.
Also noteworthy is the increased attention component testing has been getting recently. 211.84 ranked as only the twelfth most frequent citation in the 2009-2011 foreign warning letter cohort.
FDA is looking closely at how finished product manufacturers – and those making APIs as well – are overseeing not onlytheir own production and controls, but also the reliability of the materials that they are receiving from upstream.
The problems the agency is seeing in the upstream testing
and distribution practices – including the lack of integrity in testing, release, and CoAs at the supplier level – are prompting investigators to make sure during drug product manufacturing inspections that the controls are in place to catch substandard ingredients before they enter dosage processes and undermine the quality of drugs on the market. With good reason, the agency is looking to dosage manufacturers to do more policing of the materials they are using.
Field Expert Thoma Highlights Component Focus
In a presentation at the University of Georgia/FDA International GMP Conference in Athens, GA in mid-March, Office of Regulatory Affairs (ORA) National Pharmaceutical Inspection Expert Sharon Thoma highlighted the attention that both the laboratory and material handling systems are now getting, particularly during foreign inspections.
She noted that her review of foreign drug product GMP warning letters issued in FY 2012 and 2013 found that failure to meet the component testing requirements in 211.84(d)(2) was the second most frequent citation – only exceeded in the foreign letters by the potentially related finding that the facility was not meeting the analytical methods validation requirements in 211.165(e).
Reflecting its prevalence in warnings letters to topical manufacturers, component testing was the fourth leading cite across all drug product GMP warning letters issued in 2013, Atlanta District compliance official Phil Campbell reported at the Georgia conference.
Notably, component testing does not appear among the top ten 483 cites in FDA’s 2013 Turbo EIR database – it is 12th on the list – indicating that when the agency does uncover the problem, it is taken seriously.
The receipt and testing of raw materials is something she looks at “every time,” Thoma stressed.
“I look at raw materials and I say, ‘how are you testing it? Are you doing full monograph testing if the full monograph is available in the USP, or are you using the certificate of analysis in lieu of raw material testing and doing an identification exam?’”
Firms doing the latter, she cautioned, need to remember that if the ID testing has three components, they have to do all three to demonstrate that the “product is what it says it is.” She finds this a “common area where people mess up.”
Supplier CoAs Need Validating
Another common aspect of the problem is not validating the
authenticity of a supplier’s certificates of analysis.
“I do not know how many times I go into firms and they are not doing this,” the ORA expert investigator said. “They will get a certificate of analysis in, they will do an identification exam, but they do not validate the authenticity of that supplier’s CoA.”
What is needed according to the GMPs, she explained, is doing the full monograph testing at least annually. “You have to validate them for giving you a good CoA, not a bogus one,” she stressed, adding that the most difficult test is the one suppliers are “going to fudge on the most.”
A reduced component testing approach can be employed, Thoma said, “if you have a solid scientific basis for how you are doing that.”
She would not want a firm that gets 10 or 20 raw materials from the same supplier to test only one of them, even if the supplier is a trusted one with reliable CoAs.
“I would want you to have some reasoning as to why you do or do not test it, and then I would expect it to be on some type of rotating basis where, overall, you are looking at all of these.” Thoma would not “expect you to test every single thing that comes in the door,” but to have a procedure for justifying “why you are doing the testing you are doing.”
She would want to see if a firm is “either doing full monograph testing, or ID testing and using the validation of the authenticity of that supplier’s CoA.” She reminded the conference attendees that for components that are difficult to test, it may be in the firm’s best interest “to do full monograph testing, because if something goes wrong with that API or that excipient, it is going to be your end product that is majorly effected by that.”
Monograph Compliance Also at Issue
The most recent of the warning letters issued to an OTC topical manufacturer – to Goleta, California-based Recsei Labs in January – incorporates the characteristic elements.
The OTC monograph and unapproved drug sections of the letter point to one of Recsei’s products labeled for use as an anti-itch and topical analgesic drug product, which combines hydrocortisone and diphenhydramine HCl – a combination not “generally recognized as safe and effective” by the relevant tentative final monograph for the labeled use.
The letter proceeds to cite the main CGMP deviations found during an inspection six months earlier. Not establishing “the reliability of your component supplier’s analyses through appropriate validation of the suppliers test results as required by 21 CFR 211.84(d)(2)” tops the list.
The letter expresses further concern with Recsei’s not reexamining or retesting its components to show continued suitability “after being kept in storage for long periods of time or exposure to conditions that may adversely affect the components, as required by 21 CFR 211.87.”
The other problems cited are also frequently in the OTC topical mix – not establishing and following adequate procedures for stability (166(a)) and for equipment cleaning and maintenance (67(b)).
In turn, FDA’s Los Angeles District Acting Director Steven Porter notes in the letter that the corrective action commitments the firm made in response to the inspection lacked detail and implementation timeframes. Porter also commented on the repeat nature of the CGMP issues found during the inspection – a not infrequent entry on OTC topical warning letters – as warranting the firm’s getting the help of a third party GMP expert to assess its compliance.
Water Quality of Concern for Topicals
The warning letter received in December 2013 by Paterson, New Jersey-based Ameriderm Labs, which focused on the production of its topical products AmeriWash, DermaFix, Instaclean and PeriShield, is similar in: ● citing component testing first in the CGMP deviation list ● including equipment cleaning, and ● highlighting the repeat nature of the various deviations found.
As an example of not meeting 211.84(d)(2), NJ District Director Diana Amador-Toro points to the inspection finding that Ameriderm had not tested the water used in product manufacturing to ensure the absence of objectionable microorganisms since 2006. FDA’s concern was heightened in finding several microorganisms, including Pseudomonas, Cronobacter, Burkholderia and Acinetobacter, in the water samples the investigators collected during the inspection.
The firm’s response to the inspection concern was inadequate in that the firm had not sufficiently increased its water sampling and had not investigated the “root cause of the unsatisfactory microbial control” of its water system.
The district director emphasized the importance of Ameriderm’s manufacturing and testing standards, including microbial controls, for its topical products, in view of their use in hospital or nursing home settings, and their application on broken skin. As such, “these products should be consistently manufactured to minimize bioburden and be free of objectionable microorganisms,” the agency stresses. The letter notes that the 211.84(d)(2) observation was also made at the previous inspection in June 2011.
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Regarding cleaning procedures (211.67(b)), the firm was found to lack detailed instructions and logs regarding the cleaning and sanitization of non-dedicated equipment, including mixing kettles and tanks.
Ameriderm’s response to the inspection findings, in turn, was inadequate because the revised procedure provided lacked “sufficient details including cleaning agent concentrations, equipment disassembly instructions, cleaning frequency, rinse times and water temperatures,” and the firm did not provide “any information describing how the cleaning process will be documented and monitored, or your method for determining cleaning effectiveness.”
FDA also found the lab operations inadequate for testing components, in-process materials and finished products, and for not deploying scientifically-justified finished product specifications.
As in other of the OTC warning letters, the agency expressed dissatisfaction with the relationship with the contract lab on which Ameriderm was relying. FDA found that the assay methods at the contract lab for testing its finished products for release were not validated.
Process validation was also lacking (211.100(a)). The firm had not identified “the component attributes (e.g., solubility and viscosity) and the process parameters (e.g., mixing time, blending speed, and temperature) that are important to produce” the topical gel, cream and ointment products under review “with consistent quality.” Concern was also expressed with Ameriderm’s deviation investigation procedures (211.100(b)).
CoAs Need to be Confirmed
The warning letter issued to Madrid, Spain-based Jabones Pardo in August 2013 exemplifies FDA’s underlying concern that incoming materials are being accepted based on CoAs alone.
Like several other of the OTC topical producers in the 2012-2104 warning letter cohort, the firm was found not to have established the “reliability of the component supplier’s analysis through appropriate validation of the supplier’s test results at appropriate intervals,” and failing to conduct at least one specific identify test on a component when relying on the supplier’s analysis.
The letter to the Spanish firm also fits the usual model in which the incoming component testing shortfall is accompanied by inadequate product release testing, including evaluating the identity and strength of all of the active ingredients and having validated methods as required by 211.165(a).
FDA is finding that the lab work at these firms is not
The warning letters issued in 2013 to topical manufacturers Kanebo Cosmetics of Kanagawa, Japan, Peking Medicine of Hong Kong, and Cornelius, North Carolina-based V-SAB are among those following the same model – citing 165(a) on methods validation and 166(a) on the stability testing program along with 84(d)(2).
A similar nexus of GMP problems is referenced in warning letters sent to OTC oral dosage manufacturers since 2012 – usually also accompanied by concerns about monographcompliance.
Fabricated CoA Results Found in India
The reason for FDA concern with naïve reliance on CoAs is writ large in a warning letter the agency issued at the end of February to Canton Labs regarding its API facility in Vadodara, India.
Topping the warning letter was the finding during an inspection last April that Canton was reporting on its CoAs that batches were meeting microbial
Expectations for Incoming Material Testing
What CDER Office of Manufacturing and Prod-uct Quality Acting Director Michael Smedley re-quested from Jabones Pardo in responding to the letter is instructive on FDA’s overall expec-tations for incoming material testing. Drug manufacturers, and topical firms in particular, should make sure that they can provide FDA in-vestigators with the same information to fore-stall enforcement problems.
● Describe procedures for conducting at least one spe-cific identity test for each incoming lot of components before releasing it for use in your finished products.
● Include a description of your sampling procedure forraw materials and the number of samples tested for each incoming lot.
● Provide documentation that demonstrates your firmhas performed method validation for each test method.
● Provide test results of your reserve samples, within re-tention period, of each lot of API that you used in the manufacture of finished drug products distributed to the U.S. market.
● Additionally, include your API supplier qualification pro-cedures and results.
assuring the quality of the ingredients at either side of the production process. And, as at Jabones Pardo, the stability testing program is usually also deficient.
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and metal impurities limits without actually doing the testing or having any supporting data.
Further, FDA had already found similar documentation problems in its 2008 inspection of the firm, and stressed in the warning letter its concern that “proper actions” had not been taken “to address the underlying issues.”
Making the lack of integrity in the API firm’s CoAs even more disturbing was FDA’s findings of the lack of cleaning validation in non-dedicated equipment, on which apparent product residue was observed.
The warning letter goes on to cite a laundry list of other GMP and documentation deviations that further undermine the credibility of Canton’s CoA reports that its APIs conform to specs and that “compromise” the “quality and accountability” of its API “in the supply chain.”
Following the warning letter, Canton was placed on FDA’s import alert list, banning all of the products made at the Vadodara facility from entering the U.S.
API Relabeling Practices in Scope
A warning letter at t e end of January addressing practices at the Hong Kong and Tempe, Arizona facilities of API relabeler/repackager CBSCHEM shows FDA’s concerns extending a step further down the component distribution chain. The findings again shed light on why the agency is paying close attention to incoming material review at dosage manufacturers.
The letter from CDER Office of Manufacturing and Product Quality (OMPQ) Director Steve Lynn explains what the FDA’s expectations are for the repacking/relabeling facet of the API supply chain, how the firm’s practices were deficient, and what was needed regarding their correction.
A mid-2013 inspection of CBSCHEM’s Hong Kong operations revealed that records were not being retained allowing for “the complete traceability” of the APIs it was handling.
Records on about two dozen API lots were found not to contain the batch numbers, manufacturing dates, and expiration or retest dates. Also observed were “inconsistent record retention practices with regard to the original manufacturing, including the manufacturer’s identity, address, batch number, purchase, receipt, transportation, distribution, and certificates of analysis.”
The facility’s inventory records were also found to contain insufficient information, such as invoice numbers, to identify and track the APIs received and distributed by CBSCHEM.
Lynn explained that the firm’s response to the 483 did not provide sufficient detail regarding how the firm would “maintain and control appropriate supply chain reconcilability of your APIs.” He pointed to ICH’s API GMP guideline Q7 for a detailed description of the records that are needed to ensure product traceability.
Moving downstream in the firm’s operations, the letter cites the failure of CBSCHEM to “transfer all quality or regulatory information received from the API manufacturer” to its customers.
The firm’s CoAs were found to lack the identity of the original API manufacturer and the actual testing facility. Lynn added that “it is essential that a CoA include batch or lot codes, laboratory testing information, expiry or retest dates, and other relevant information.”
The CDER official asked that the repacker/relabeler respond by providing written procedures for the transfer of quality and regulatory information to customers. CBSCHEM needed to explain how it would ensure the information is accurate and complete. The firm was asked to “provide specific details of the information you will transfer, and how you will transfer it to your customers, most notably through creating an adequate CoA.”
The other two entries in the Hong Kong section address CGMP deficiencies in the repacking/relabeling and holding operations themselves.
The operations were not controlled sufficiently to avoid mix-ups and loss of API identity, FDA maintained – for example, storing unlabeled APIs in inadequately labeled totes, and storing returned APIs in the same shelves as incoming APIs without clear separation or identification.
The facility was also found not to have a quality unit that would be responsible for reviewing and approving CGMP documents and procedures and assuring product quality. In the response to the letter, Lynn asked for written quality unit procedures that would assure that the CGMP requirements were met (see box below).
On CBSCHEM’s Tempe, AZ inspection, the warning letter highlighted the findings that a container labeled as an excipient was tested by FDA and found to actually contain several different APIs – a mislabeling incident that could pose “a severe hazard to consumers.”
Also highlighted was the Tempe facility’s inability to provide “basic documents that must be retained, including those with the identity and address of the original manufacturer,” such as CoAs and “other records with critical information regarding the ingredient(s).”
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As in other recent warning letters, FDA “strongly” recommended that CBSCHEM’s executive management “immediately undertake a comprehensive evaluation of [its] global operations to ensure compliance with CGMP requirements,” and “engage a third party consultant with appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems.”
The letter goes on to point out the potential consequences of the non-compliance at the repackaging/relabeling stage to the downstream purchasers – underscoring the importance of drug manufacturers paying close attention to how the materials they are using are being handled throughout the distribution chain.
The letter warns that “until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API labeler/relabeler.” The letter adds that the failure to correct the deficiencies may result in FDA continuing to refuse admission to the US of materials from the Hong Kong facility.
Incoming Material Testing Also Cited at API Firms
The review of incoming materials is being looked at during
foreign API inspections as well.
The issue was raised, for example, in a warning letter to API manufacturer Asada Milling Company of Gunma, Japan, issued in March 2013, which stemmed from an inspection conducted the previous October.
As part of the weakness in Asada’s quality oversight and procedures outlined in the letter, the firm was cited for not routinely performing identity testing on incoming raw materials to be used in its API manufacturing and not verifying the reliability of CoAs for these materials “at appropriate intervals.”
The letter also points out that Asada did not have “established procedures that describe the receipt, identification, quarantine, or storage of raw materials,” nor had it established specs for the raw materials or finished APIs.
Other concerns at Asada involved: ● inadequate equipment and facility cleaning ● incomplete batch records and not assigning of unique batch identification numbers ● not meeting the stability program and expiry/retest assignment requirements, and ● not performing process validation for critical manufacturing parameters. Regarding the latter, FDA asked the firm to submit validation protocols for all of its APIs, a timeline for execution, and a description of how a continued process verification program would be “implemented that will verify that your API manufacturing processes remain in an ongoing state of control.”
As in other foreign API warning letters, the Asada letter states that FDA would continue to refuse admission of APIs manufactured at the firm, and may withhold any new drug applications or supplements listing the firm as a supplier, until all the corrections were confirmed.
A warning letter issued to Hyderabad, India-based Posh Chemicals in August 2013 demonstrates that FDA is also looking at whether the methods that are being used to assess incoming raw materials are validated.
Along with significant concerns about the integrity of Posh’s lab data and related controls, the letter cites the inspection findings that the lab was using non-validated assays for testing of key starting materials and for an intermediate used in API production.
FDA asks the firm to submit reports demonstrating the “scientific validity” of these methods, along with a review of the “validation status of all other non-compendial analytical methods used in your laboratory” and a timeline for completing the validation activities.
Quality Unit Oversight at API Repackers/Relabelers
● approving or rejecting all APIs, packaging and labeling materi-als
● reviewing completed batch and lab control records before de-termining if an API lot can be released
● ensuring that discrepancies, complaints, returns, and failuresare investigated and resolved
● approving all specifications
● approving all procedures affecting the quality of APIs
● approving raw material vendors, API contract manufacturers,contract labs, and other outsourced activities
● approving changes that potentially affect API quality for theiracceptability
● making sure that materials are appropriately tested and the re-sults are reported
● making sure that there is stability data to support retest orexpiry dates and storage conditions of APIs
In the warning letter to CBSCHEM, CDER compliance official Steve Lynn lists the following as the oversight activities expected to be performed by a quality unit at a repacking/ relabeling facility in the API distribution chain:
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Future USP Global Education and Training Courses, Meetings, Workshops and More!
Global Education and Training Courses
Featured Classroom Courses
§ Brazil: Excipient Performance; Developing and Validating Dissolution Methods
§ China: Essentials of Compendial Microbiology Testing; Analysis of Elemental
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§ Europe: In-Vivo In-Vitro Correlation (IVIVC); HPTLC for Identification
of Articles of Botanical Origin
§ India: Pharmaceutical Stability; Effectively Using USP–NF; Practical
Applications of Chapter <467> Residual Solvents
§ United States: Effectively Using FCC; Good Manufacturing Practices;
Analysis of Elemental Impurities; Dissolution: Theory and Best Practices
Webinars Increase your knowledge of compendial activities!
The USP Global Education and Training Department has launched a series of webinars to increase distance learning opportunities for the pharmaceutical industry. These sessions are conducted by USP Scientific Liaisons or Expert Committee Members who are directly involved in the standards-setting process.
For Classroom Course Information and Schedules Contact [email protected], or visit www.usp.org/meetings-courses/courses and click on the appropriate language if other than English. All Europe offerings are available in English. For India offerings, contact George Mathew at [email protected].
FOR MORE MEETING AND WORKSHOP INFORMATIONVisit www.usp.org/meetings, contact [email protected] or call +1-301-816-8130.
NOTE: Events held at USP Headquarters, Rockville, MD (U.S.) unless otherwise indicated. Courses, symposia, workshops and dates subject to change.
USP Workshop Series
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§ Dissolution Testing of Capsules
June 2–3, 2014§§ 6th Bioassay Workshop
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Standards and Quality
November 5–6, 2014 § Contaminants in Foods–Compendial
Approaches to Protect Public Health
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A bolus of FDA warning letters to injectable compounding operations in the first quarter of 2014 has followed in the wake of the agency’s 2013 inspection blitz of high-volume sterile pharmacy compounding operations nationwide and legislative empowerment through the Drug Quality and Safety Act (DQSA), signed into law in November.
Nine of the 11 drug GMP warning letters issued in 2014 that were posted by FDA through March went to injectable compounders.
The 2014 warning letters contain similar language explaining the regulatory policy environment that compounders are operating in, given the new authorities granted to FDA in DQSA (see IPQ “Monthly Update” Nov./Dec. 2013, pp. 28-30).
The agency explains in the letters that at the time the recipients were inspected in 2013 prior to DQSA’s passage, there were “conflicting judicial decisions regarding the applicability of section 503A of the FDCA [21 U.S.C. § 353a], which exempts compounded drugs from several key statutory requirements if certain conditions are met.” Title I of DQSA – referred to as the “Compounding Quality Act” (CQA) – the agency notes, amended that section of the Act by eliminating the advertising restrictions that had been the basis for the judicial conflicts.
FDA Transparent on Compounding Enforcement
On December 4, a week after the law was signed, FDA issued three draft guidances and three companion Federal Register (FR) notices related to the implementation of the compounding provisions of the act (ibid.)
The draft guidances and FR notices drew a wide array of comments that reflect the complexity of the factors and the various stakeholders that need to be considered in advancing the regulatory processes for compounding (see story on p. 40).
A draft guidance on the fees required for inspections and re-inspections of outsourcing facilities was released on April 1 with a comment period extending through May.
The speed at which the agency is moving in the act’s implementation reflects the central place that compounding operations have occupied on FDA’s inspection and health protection radar screen since the fall 2012 meningitis outbreak caused by fungus-contaminated injectable methylpredisone
Wave of FDA Warning Letters to Injectable Compounders in Q1 2014 Follows 2013 Inspection Blitz and Legislative Empowerment; Recipients Among Those Applying for Outsourcing Status
produced by NECC (see IPQ Special Report November, 2012).
In addition to speed, FDA is also exhibiting a high degree of transparency in its enforcement actions related to compounders.
The agency has assembled a comprehensive public database that is updated in nearly real time and contains a list of all compounding firms that have been inspected since FDA’s inspection blitz began in the wake of the meningitis outbreak (see IPQ “Monthly Update” March 2013, pp. 11-34) – 82 as of the end of March – with links to related: ● 483s (issued to all 82 of the inspected facilities) ● warning letters (34) ● recall notices (26) ● FDA and company press releases (12), and ● referral letters to state boards of pharmacy with recommended follow-up actions (7).
Included in the 34 warning letters are 15 citing GMP concerns and 19 from 2008 to 2012 primarily addressing misbranded and unapproved drugs and label claims. Also listed with links are 483s given in 2012 and 2013 to five contract testing laboratories used by compounders.
Outsourcing Rules and Fees Clarified
FDA is also being transparent on the firms that are registering as outsourcers – a new category of compounder provided for in DQSA to allow a middle ground between a traditional pharmaceutical manufacturer and a traditional pharmacy compounder in recognition of the larger-scale interstate hospital supply operations that have expanded in the US.
Under section 503B of the new act, an outsourcing facility: ● is engaged in the compounding of sterile drugs ● has elected to register as an outsourcing facility ● complies with all of the requirements of section 503B ● is not required to be a licensed pharmacy, but compounding must be by or under the direct supervision of a licensed pharmacist, and ● may or may not obtain prescriptions for identified individual patients.
FDA’s draft guidance explains that compounders registering as outsourcers will be inspected by FDA according to a risk-based schedule. Along with complying with the drug product CGMPs, they must meet certain other requirements, including reporting adverse events and providing FDA with certain information about the products they compound (see IPQ “Monthly Update” Nov./Dec. 2013, pp. 28-30).
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recognized as meeting the requirements, “outsourcers” qualify for exemptions from the new drug application and labeling requirements, and are able to offer the assurance to hospitals and other health care providers that their operations were subject to federal CGMP oversight.
Registration, the draft guidance points out, indicates that all the required paperwork has been submitted to the agency, but does not imply that the firms have been granted the outsourcing status. Follow-up inspections, payment of fees, and other conditions must be met for the firms to become exempt from the approval and labeling requirements as set forth in DQSA.
The new user fee draft guidance proposes a $15,000 annual establishment fee for outsourcers, or $5,000 if the firm qualifies as a small business as defined in the draft. Should a re-inspection be required, the cost would be $15,000, independent of the size of the business.
The guidance explains that outsourcing facilities that register prior to October 1, 2014 – the end of the government’s 2014 fiscal year (FY) – will not have to pay a fee for FY 2014. They will, however, need to pay the fee for FY 2015. Payments are due by the end of the calendar year and are not pro-rated.
Failure to pay a user fee will result in the facility losing its status as an outsourcing facility, the draft explains.
Warning Letters, Recalls do not Preclude Registering
As of the beginning of April, 38 firms had registered with FDA as outsourcers.
Of the 38 registered firms, five have received GMP warning letters: ● Avella of Deer Valley (Phoenix, AZ) ● Olympia Pharmacy (Orlando, FL) ● Triangle Compounding Pharmacy (Cary, NC) ● Medi-Fare Drug & Home Health Center (Blacksburg, SC) and ● Allergy Laboratories (Oklahoma City, OK) – a registered drug manufacturer and BLA holder that produces sterile products.
Of the remaining 33 registered firms, 15 have received 483s and may be subject to other further compliance actions, 17 have not yet been inspected, and one – Unique Pharmaceuticals in Temple, TX – was inspected in May 2004, and no 483 was issued.
Three of the registered firms have conducted recalls due to the FDA inspections.
These include two that have received warning letters: ● Olympia Pharmacy, which conducted a multi-state recall in May 2013 of all sterile products compounded between December 2012 and March 2013 due to concerns about sterility assurance, and ● Avella of Deer Valley, which conducted a nationwide recall of two medications due to concerns with sterility testing at the contracted lab in September 2013. A third registered oursourcer, JCB Laboratories, of North Wichita, KS, recalled six drug product lots for the same reason as Avella.
Additionally, 19 other recalls were performed by 14 compounders in 2013 – the majority due to FDA findings of a lack of sterility assurance. Including Avella and Olympia, four of the 14 recalling firms received warning letters. The remaining 10 received FDA 483s.
Key Concerns in Compounding Warning Letters
The following chart includes the CGMP concerns, recalls, and outsourcer registrations among the 15 compounders that received GMP warning letters since 2012.
Firm Date EM Contamina�on Gowning Stability Recall Outsourcer
Infupharma 7/12 X X X X
Medi-Fare 3/13 X X X X X
Custom Compound 5/13 X X X
Balanced Solu�ons 7/13 X X X X X
Green Valley 8/13 X X X X X
Stewart Compound 8/13 X X X X
Avella 1/14 X X X X X
Triangle 1/14 X X X X X
Olympia 2/14 X X X X X X
Nora 2/14 X X X X X
Pallimed 2/14 X X X
Total Pharmacy 2/14 X X X X
Village Fer�lity 2/14 X X X
Wedgewood 2/14 X X X
Pentec 3/14 X X X
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�01� Warning Letters Show Commonalities
In addition to the common language in the majority of the 2014 warning letters explaining FDA’s new regulatory authorities granted under the DQSA, six of the nine letters cited the manufacturing and distributing of products without valid prescriptions for individually-identified patients. The agency explains that as these products are not the subject of approved applications, they are rendered unapproved new drugs and misbranded.
The majority of the letters contain a series of sections that address: ● compounded drugs under the FDCA ● violations of the FDCA ● unapproved new drug products ● misbranded drug products ● adulteration charges – the section in which the main GMP concerns are explicated ● corrective actions, and ● the agency’s conclusions.
Each of the warning letters cited “insanitary conditions” or “serious deficiencies” in aseptic practices in the compounding of products “that were intended or expected to be sterile, which put patients at risk.”
Along with Avella and Olympia, other recipients of the warning letters were: ● Nora Apothecary and Alternative Therapies (Indianapolis, IN) ● Pallimed Solutions (Woburn, MA) ● Pentec Health (Boothwyn, PA) ● Total Pharmacy Services (Houma, LA) ● Triangle ● Village Fertility Pharmacy (Waltham, MA), and ● Wedgewood Village Pharmacy (Swedesboro, NJ).
In the letters to Pallimed, Pentec, and Village Fertility Pharmacy, the focus was primarily on unsanitary conditions observed during the inspection, including aseptic breaches. No reference was made to the agency’s new authorities or valid prescriptions. None of these three firms has applied for outsourcer status.
In each of the nine letters, FDA “strongly” recommended that the firm’s management under-take a “comprehensive assessment” of its manufacturing operations, including facility design, procedures, personnel, processes, materials, and systems.
“In particular,” the letters note, the review should assess the acceptability of the aseptic processing operations. It is advised that “a third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation.”
As with most domestic GMP warning letters, this cohort was signed by the director of the FDA district in which the receiving facility is located.
At the University of Georgia/FDA International GMP Conference in March, Atlanta District
Supervisory Consumer Safety Officer Philip Campbell reviewed enforcement data from 2013, including the agency’s compounding pharmacy inspection effort.
In his review of the compounding warning letters issed dur ng the year, Campbell noted that a few trends “popped up ped up immediately.”
Environmental monitoring (EM) and potential microbial contamination were cited in all seven letters. Gowning was addressed in six, and stability testing in five.
An analysis of the nine warning letters issued to compounders in the first quarter of 2014 shows a similar pattern. All nine were cited for EM and contamination concerns, eight for gowning, and four for stability testing[see box at right containing this analysis for all 15 GMP warning letters issued to compounders since 2012].
A comparison of IPQ’s analysis of the initial results of FDA’s 2013 sterile compounding inspection initiative (see IPQ “Monthly Update” March 2013, pp. 30-34) with the top 2014 warning letter citations reveals a significant overlap.
The top citations in the first 14 483s issued under the initiative in order of occurrence were: ● gowning ● personnel practices ● EM ● sterility/endotoxin testing ● media fills ● investigations, and ● validation of sterilization.
A subsequent analysis by IPQ of seven compounders that conducted recalls between March and May 2013 showed the most prominent 483 observations in that cohort to also include aseptic personnel practices, contamination control, gowning, and sterilization validation (see IPQ “Monthly Update” May 2013, pp. 34-41).
Comparing the top concerns raised in the 483s with those in the 2014 warning letters shows the prevalence of environmental monitoring and gowning in both. In turn, the microbial contamination potential mentioned in the warning letters in most cases resulted from the personnel practices and/or lack of validation of sterilization cited in the initial 483s.
Inspection Crackdown Results in One Consent Decree
So far, one consent decree has been signed in the wake of the FDA’s inspection crackdown on compounders – with Med Prep Consulting of Tinton Falls, New Jersey, in June.
Med Prep received a warning letter in July 2010 highlighting concerns over the firm’s practice of repackaging sterile products without registering with the agency as a repackager.
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A 483 followed after a March 15 to April 3, 2013 inspection, during which all of the firm’s sterile compounded drugs were recalled due to the potential for mold contamination.
In addition to compounding products without a patient-specific prescription and distributing products across state lines, the 483 and consent decree cited insanitary conditions and numerous other GMP violations.
FDA analyses of product samples taken during the inspection found mold in injectable drug products labeled as sterile,
and revealed that some of the products were sub-potent, the consent decree noted. Med Prep has not registered for outsourcer status.
DOWNLOADS FROM THE STORY:
• FDA compounding enforcement database (con taining ���s, warning letters, recall notices, press releases, and FDA referral letters to state boards of pharmacy)
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Draft guidances and Federal Register (FR) notices issued by FDA in December to help implement the compounding provisions in the Drug Quality and Safety Act (DQSA) drew a wide array of comments that reflect the complexity of the factors that need to be considered in advancing the regulatory processes for compounding.
The three draft guidances and three FR notices that were issued in early December (see IPQ “Monthly Update” Nov./Dec. 2013, pp. 28-30) received significant numbers of comments from across the broad spectrum of stakeholders impacted.
The draft guidances cover: ● overarching rules for what constitutes pharmacy compounding and how enforcement for violations may be applied ● a definition of a new category of compounder created by the DQSA – an “outsourcing facility” – and the registration requirements, and ● interim requirements for ongoing reporting of information to FDA by the outsourcers on their products and services.
One of the FR notices requests nominations for “difficult-to-compound” drugs. The other two provide instructions and a template for completing the nominations. The comment periods ended in early February for the draft guidances and early March for the FR notices.
�� Stakeholders Comment on Umbrella Guidance
The umbrella guidance received comments from 37 stake-holders, 34 of which have been posted. The 34 comments were submitted by 20 associations, nine pharmacies, and five individuals.
Some common themes include: ● concerns that FDA may be restricting the practice of compounding drugs for office use without individual prescriptions ● the need for clarification of key terms, and ● requests for clarification regarding FDA’s intent to establish memoranda of understanding (MOU) with the states that “will address the interstate distribution of inordinate amounts of compounded drug products.”
The International Academy of Compounding Pharmacists (IACP) and the American Pharmacists Association (APhA) weighed in on the ability of pharmacies to compound products for office use rather than to specific prescriptions.
Each commented that they understood FDA will be drafting additional guidance regarding office use of compounded products, but expressed concerns regarding the agency’s thinking in light of a December 3 stakeholder call in which
CDER Office of Regulatory Policy (ORP) Associate Director Jane Axelrad responded to several questions regarding office use in a fashion that seemed to imply that FDA does not intend to allow it.
IACP stated that it is “very concerned that FDA does not intend to allow a pathway in which health care professionals, hospitals, and other health facilities may purchase compounded drugs from pharmacists without prescriptions in order to administer the compounded medications within the health care facility under 503A.”
The association maintained that the “Congressional intent” was “to leave the issue of providing compounding medications by pharmacists for a prescriber’s administration to, or treatment of, a patient, within their practice to the states.”
A request for clarification of key terms was made by several commenters, including the Patient, Consumer, and Public Health Coalition (PCPHC), the Biotechnology Industry Organization (BIO), and IACP.
PCPHC voiced general support for the umbrella guidance, but requested clarification of the terms “limited quantities,” “inordinate amounts,” and “valid certificate of analysis.” BIO echoed a request for clarification on “limited quantities” along with “essentially copies of commercial drug products,” and “regularly.”
IACP requested clarification on “inordinate amounts” and maintained that “since the most recently passed legislation was not accompanied by a Committee Report, it is essential when defining ‘inordinate amounts’ to look back at the Senate Committee Report for the Food and Drug Administration Modernization Act of 1997.”
The 1997 report offers guidance to FDA and defines “inordinate quantities” as the “amounts typically associated with ordinary commercial drug manufacturing.” Taking this definition into account, IACP “would strongly oppose any attempt by FDA to impose an arbitrary percentage or quantity limitation on the amount of compounded medications that may be distributed interstate.”
MOUs Should be Publicly Available
The guidance statement in the umbrella guidance that MOUs with the states will be drafted that “will address the interstate distribution of inordinate amounts of compounded drug products” drew comments from compounder PharMEDium,
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the associations BIO and APhA, and Pew Charitable Trusts.
PharMEDium suggested that “in the interest of transparency, and ultimately public safety, that information displaying the state-negotiated MOUs and any enforcement actions taken for violations of its terms appear on the FDA website.”
It maintained that making the information publicly available “will help ensure that those pharmacy compounding operations that are not operating within the contours of section S03A of the Act, but rather are operating more like a 503B Outsourcing Facility, be categorized and regulated under the appropriate regulatory framework (i.e., section 503B).”
BIO echoed PharMEDium’s request that the MOUs be publicly available, and requested that FDA “act as expeditiously as possible to establish the state coordination and MOU process.”
In its comments, APhA “strongly encouraged” FDA to “promulgate the draft MOU subject to comment, to provide an opportunity for all stakeholders, including but not limited to the National Association of Boards of Pharmacy (NABP), State boards of pharmacy, and pharmacists to offer input.” The association also attached the comments it had provided to a draft MOU that FDA released in 1999.
Pew Charitable Trusts provided suggestions on what it feels should be covered in an MOU between FDA and the states.
Pew encouraged FDA to consider including “alternate parameters in the MOU to address high-volume, high-risk compounding.” It suggested the agency include a focus on: ● compounders that primarily produce office stock productsor compound in anticipation of prescriptions at a large scale ● compounders that sell to another dispensing entity ratherthan dispensing drugs directly to patients, and ● sterile versus non-sterile compounding.
Pew also maintained that MOUs should ensure states share information with the FDA on known and potential violations of federal statute and serious adverse events. It pointed out that Section 105 of DQSA requires FDA to establish a process for the agency and states to share information on identified violations of 503A as well as any actions taken against compounders, but that the information-sharing is voluntary for states
“MOUs should require states to provide this information to the FDA, and should additionally require the sharing of information on potential violations of 503A to help direct FDA oversight, as well as serious adverse events related to compounded products,” Pew commented.
Outsourcing Guidance Prompts Sterility Questions
Prominent among the comments on FDA’s draft guidance on registration as a compounding outsourcing facility were questions regarding why only sterile product compounders are in scope, and a provision allowing firms other than licensed pharmacies to register. Seven organizations submitted comments, including one association and six compounders.
Westlake Village, California-based Sinus Dynamics Pharmacy and IACP questioned whether non-sterile compounding facilities are in fact covered by the guidance.
IACP commented that while DQSA section 503B only allows facilities in the practice of sterile compounding to register, the draft guidance states that an outsourcing facility must notify FDA whether the outsourcing facility “compounds sterile drugs.”
The association stated that it is “confused as to whether other facilities that do not compound sterile compounds are allowed to register,” noting that if only facilities that compound sterile drugs are allowed to register, “then the requirement of notification to FDA that one compounds sterile drugs seems redundant.”
IACP also expressed “strong concerns” with a statement in the draft guidance that allows an outsourcing facility not to be a licensed pharmacy.
The draft states that “the outsourcing facility is not required to be a licensed pharmacy, and may or may not obtain prescriptions for individual patients.”
The association asked for “further guidance” on whether this language would allow a non-pharmacy to fill prescriptions. It also requested clarification on whether FDA interprets the statement to mean that FDA has the authority to regulate both dispensing and compounding within a 503B registered facility.
Allergy Laboratories of Oklahoma City, OK is an example of a firm that registered as an outsourcer but is not a compounding pharmacy.
Allergy is a registered drug manufacturer and BLA holder that produces sterile products. The firm was among five firms that have registered that have received a warning letter addressing GMP issues since the end of March. (see p. 36 for more on the results of FDA’s inspection crackdown in the
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sterile pharmacy compounding arena.)
Interim Reporting Requirements Questioned
FDA’s draft guidance on interim reporting requirements for registered outsourcers received comments from seven compounders.
Among them were questions regarding the timing of report submissions to the agency and assertions that the new requirements will not decrease the likelihood of the issues that led to the pharmacy compounding crisis that precipitated the renewed compounding focus.
PharMEDium pointed out that the draft requires each registrant to submit a product report to FDA in June and December of each year, while it also specifies that the report must identify all drugs compounded during the previous six-month period.
“Taken together,” the compounder asserts, the statements place a burden on the compounder if the reports are expected to be inclusive of materials compounded during the month the report is submitted. It suggests that the agency allow a “minimum of 30 days to compile and audit” the information prior to submission. It further suggests that the reporting be aligned with annual business processes and Drug Enforcement Agency (DEA) reporting.
PharMEDium further suggested that the date a compounded drug is shipped out of the outsourcing facility is “the most appropriate date” to report to the agency as the compounding date “to accurately reflect the production and consumption process.”
The Academy of Managed Care Pharmacy (AMCP) asserted that the outsourcer registration guidance “does not provide assurances to the public and would not have likely prevented the tragedies in 2012.”
AMCP commented that it has “consistently maintained that the FDA had the authority to address the fungal meningitis outbreak and that additional authority was not necessary.” It asserted that the passage of DQSA “created confusion by creating a new, unnecessary outsourcing facility that represents only an administrative registration requirement with no further assurances of safety and efficacy of compounded products.”
The association further maintained that DQSA “creates a dual regulatory scheme,” under which “some pharmacies will be licensed entities under state law and also registered under federal law. Other non-pharmacy entities may seek
registration, but the public is not adequately informed of the company’s business practices or pharmacy status.”
AMCP concluded that it “believes this regulatory infrastructure will create complications in administration and that issues of responsibility and accountability will undoubtedly continue to occur.”
Comments Also Heavy on “Difficult-to-Compound” List
FDA’s December FR notice requesting nominations for a list of products that present demonstrable difficulties for compounding that may result in an adverse effect or the safety or effectiveness of the product the risks – the so-called “difficult-to-compound” list – received comments from 32 different organizations and individuals.
The submissions included nominations of particular compounds as well as suggestions for alternative approaches to determine which products are difficult to compound as opposed to producing a finite list.
Substances that were nominated for the list (and the submitting firm) include: ● hyaluronidase for injection and hyaluronidase injection (Halozyme) ● Collagenase SANTYL® Ointment (Smith & Nephew) ● dimethyl fumarate (Biogen Idec) ● deoxycholic acid and its salts (Kythera Biopharmaceuticals) ● methylprednisolone for epidural injection (ArachnoiditisSociety for Awareness and Prevention) ● injectable erectile dysfunction drug combinations containing papaverine (Auxilium Pharmaceuticals), and ● atropine, heparin, and azithromycin reconstitution as a powder for IV infusion (Nephron Compounding Center).
In its comments, BIO asserted that all biologicals should be included on the list. The association requested that FDA “formally state that biological products subject to FDA approval under section 351 of the PHSA are not covered by the limited new drug application exemptions found in FFDCA sections 503A and 503B, and thus compounding these products without an approved BLA is prohibited and would constitute illegal manufacturing.”
The American Society of Health-System Pharmacists (ASHP) and PharMEDium suggested some general approaches to determining what products are difficult to compound rather than submitting specific examples.
ASHP commented that it “supports FDA’s approach of evaluating candidates for the list on a case-by-case basis using its stated criteria as well as other factors that may emerge depending on the array of agents or formulations
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proposed for the list.”
The association maintained that, in general, the criteria for factors that present “demonstrable difficulties” for compounding proposed by FDA “represent a reasonable approach.” It requested that the agency clarify the terms “sophisticated,” “complex,” and “significant,” and explain how the degree to which these apply may vary according to the availability of newer compounding techniques or technology.
PharMEDium suggested that the agency base its determination of difficult-to-compound products in the sterile arena on the increasing risk levels involved in the continuum of sterile compounding, “from, on the one hand, producing a final sterile product combining only FDA-approved finished sterile drugs, to the higher risk start of the compounding process using non-sterile bulk substances to creating sterility in the final product.” It pointed out that “as compounding risk increases, the procedures, processes and training required to demonstrate competency in compounding should increase as well.”
Categories Approach Suggested
Public Citizen and GlasoSmithKline (GSK) recommended in their comments that FDA use categories of compounds rather than a discreet list and provided their rationale and examples.
GSK suggested the following categories: ● respiratory drugs ● modified-release drugs ● certain drugs and drug products, including but not limited to those subject to Risk Evaluation and Mitigation Strategies (REMS), and ● drugs that are characterized by narrow margins between their effective and toxic doses.
The firm pointed out that respiratory products often incorporate “sophisticated drug delivery systems,” such as dry powder or metered dose inhalers, which are “precisely engineered and tightly controlled to deliver their active ingredients to local sites of action within the body.”
In addition to their device components, the formulations of respiratory medicines “are often complex, using active and inactive ingredients with defined particle size profiles and other qualities that are intended to interact with those components in specific ways.” It asserted that the manufacturing of respiratory products “requires sophisticated facilities and equipment, and highly trained personnel, beyond the capabilities of drug compounding operations.”
Modified release products – including delayed, sustained,
and extended release tablets and capsules – are “generally manufactured using complex, often patent-protected, technologies,” GSK stressed. “The failure of a drug compounding operation to understand, have access to, and utilize these technologies appropriately could result in products with poor dosing accuracy, bioavailability, or product-to-product uniformity – any of which may affect safety or effectiveness.”
The category that includes “certain drugs and drug products, including but not limited to those subject to Risk Evaluation and Mitigation Strategies (REMS),” the pharma firm maintained, present increased risks. “Adequate mitigation of these risks requires careful and consistent manufacturing, enhanced labeling and risk communications, and even restricted distribution.”
The fourth category that encompasses drugs characterized by narrow margins between their effective and toxic doses also includes others that require careful dose selection and titration. For drugs in this category, “even small differences in dose or bioavailability can have clinical consequences for patients,” GSK maintained, citing anti-epileptic drugs (AEDs) as perhaps the most well-known of such products.
Public Citizen expressed a “concern that the FDA intends to develop and publish a single list of drug products and categories of drug products that cannot be compounded because they present demonstrable difficulties for compounding,” and recommended using product categories instead.
Like GSK, Public Citizen recommended dry powder inhaler and modified release or time-released dosage form categories. It recommended four other categories, including: ● non-sterile-to-sterile compounding ● metered dose inhaler(MDI) products ● transdermal delivery systems (TDSs), and ● enteric-coated preparations.
Non-sterile-to-sterile compounding, the consumer advocacy organization asserted, requires sophisticated facilities and equipment that must be maintained to exacting standards, rigorous training of the personnel performing the operations, and appropriately-conducted sterility assurance testing. It further referenced the problems found during FDA’s 2013 inspection blitz of sterile compounders (FISH) as evidence that this category of product deserves special attention.
Public Citizen recommended an MDI category because the drug delivery systems are “sophisticated” and “require extensive development to ensure dosing accuracy and reproducibility.” In addition, “precise formulation of the drug product” is required to ensure the dosing accuracy and reproducibility, and product-to-product uniformity is “critical, and is usually difficult to achieve.” Also cited was
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the difficulty in achieving reproducible bioavailability of the compounded drug.
In recommending a TDS category, Public Citizen cited an FDA concept paper from 2000 that recommended TDS products “be identified as presenting demonstrable difficulties in compounding.” Similarly to MDI products, TDSs are complex products that require extensive development to ensure dosing accuracy and reproducibility, and precise formulation of the drug product is required to achieving reproducible bioavailability.
An enteric-coated preparations category was recommended because improperly formulated enteric-coated preparations could impact bioavailability, potentially reducing the drug’s efficacy or increasing safety risks. Public Citizen stressed that clinical testing is necessary to prevent these problems,
DOWNLOADS FROM THE STORY:
Dockets for draft guidances (including comments): • Umbrella guidance on pharmacy compound-
ing of human drug products• Registration for human drug compounding out-
sourcing facilities• Interim product reporting for human drug com-
pounding outsourcing facilities
Dockets for draft guidances (including comments):• Drug products that present demonstrable difficul-
ties for compounding
but such testing is not required under the new compounding legislation.
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Root causes of the problems in the pharmacy compounding arena range from the absence of training in pharmacy schools to commercial pressures that prompt established pharmaceutical firms to leave the market and force hospitals to rely on less qualified providers to fill their immediate patient needs, Merck Engineering BioSterile Validation Director Chris Smalley commented at the April PDA annual meeting held in San Antonio, Texas.
Smalley’s insightful analysis of the current high-profile issues in the compounding arena was informed by both his extensive pharma experience as well as by the first two decades of his career, which was spent in the U.S. military as a licensed pharmacist performing hospital compounding.
As a hospital pharmacist, Smalley prepared IVs and total parenteral nutritional (TPN) packages. He explained that his training in pharmacy school in the 1970’s included laboratory courses that taught various types of compounding and evaluated the student’s ability to perform them.
“I couldn’t pass compounding lab until I could make capsules,” Smalley commented. “We made suppositories. We made powder…. And we made sterile products,” including hand-filling ampules with syringes. “I learned about aseptic technique.”
Over the intervening three decades, the pharmacy school curriculum has shifted towards clinical pharmacy – focused on drug/patient issues – and hands-on pharmacy compounding is no longer usually taught, he pointed out.
Smalley commented during the Q&A after his presentation that pharmacists and those inspecting them – especially at the state level – generally have not had the training or the skills to either perform compounding or evaluate those who do.
“The New England Compounding Center (NECC) was inspected by the Massachusetts State Board of Pharmacy several times,” he pointed out, and “it continued to operate.”
Pharmacists have a role in healthcare, “but they are not being taught compounding pharmacy anymore. And yet a pharmacist goes out and gets a license and is entitled to do things like making TPN solutions and do compounding. It is a real concern of mine.”
Smalley explained that the American Society of Healthcare Pharmacists published a book that provides instructions
on how to perform various types of compounding. “I don’t think reading a book would help you manufacture sterile products in your facility. They might have book knowledge, but it has a lot to do with skills.”
USP Forum Also Stresses Training Concerns
At a two-day forum on microbiology that took place at USP headquarters in Rockville, Maryland in March, 2013, a panel of experts that was convened to review compounding issues also pointed to training in pharmacy compounding as a key driver of the sterility issues that have been surfacing (see IPQ “Monthly Update” May 2013, pp. 23-33).
In focus during the session were the aseptic practice, training, laboratory and regulatory concerns that have surfaced among sterile compounders in the US and how the 2008 version of USP’s sterile compounding chapter <797> should be refined to help address them.
A basic message that emerged is that, compared to pharmaceutical manufacturers, the technicians doing sterile pharmacy compounding have a much harder job with generally much less training and expertise to accomplish it.
Participating on the panel were two members of USP’s Sterile Compounding Committee, Keith St. John and Erik Kastango, and two members of the USP Microbiology Expert Committee to which it reports, Jim Agallaco and Russ Madsen. Kastango is heading the committee that is looking at revising USP <797>.
“Pharmacy schools do not train pharmacists on aseptic processing or control or sterility assurance,” Kastango commented. “All of that stuff is tribal lore. It is verbal tradition. So it is going to be, ‘I go to my new tribe. I go to my new facility. And I am going to get trained by Keith. And I am now here. Keith leaves and Russ gets hired and so now I am going to train Russ.’ So you have this rotation over time of what people understand.”
Madsen supported the training observation with data from a Wall Street Journal article that reported on a study looking at contamination rates in pharmacy compounding operations.
The study showed that pharmacists who were doing media fills in compounding had a contamination rate of about 4%. For technicians in the same pharmacies, the contamination rate was about 8%. “Compare and contrast that with what we see in the pharmaceutical industry for aseptic processing.
Compounding Drivers and Problems Dissected by Merck Pharmacy Expert at April PDA Annual Meeting
It is down around 0.1% or better,” Madsen emphasized.
“So we see orders of magnitude differences. And I relate this to training and skill, and trying – without the benefit of scale-up, without the benefit of process development, working with a very wide variety of materials and products – to produce sterile compounded products. It is very difficulton its face.”
Cost Pressures, Shortages Drive Compounding
During the Q&A at the April PDA meeting, Smalley also pointed to changes that have taken place in the pharmaceutical industry over time that have driven the growth in pharmacy compounding, including less pharmacist presence, an increasing focus on costs and profits, and the resulting drug shortage problems.
In the 1970’s as a newly-graduated pharmacist, Smalley had the opportunity to tour pharmaceutical plants. At that time, “the head of packaging was a pharmacist. The manager of production was a pharmacist. The manager of quality was a pharmacist. There used to be a very nice interconnection between industry and pharmacy. It has become very separated. It has become difficult for us to talk.”
At that time, Smalley recounted, Parke Davis and Eli Lilly were the two largest pharmaceutical manufacturers. “They made everything. I could buy ammonium chloride in perchlorate tablets,” taken by people with tuberculosis to improve their airflow. “I am sure that it was not a big contributor to the bottom line. But that was the focus of pharmaceutical companies like Parke Davis and Eli Lilly – to make product available that met the need of patients.”
In “most” pharma companies today, Smalley maintained, the focus has shifted to the financial contribution of products to the company’s bottom line, with products periodically dropped that meet patient needs but are not profitable. Compounding pharmacies step in to fill the gaps when these products that patients need are not commercially available.
The decreased profits from products with thin margins and those about to go off patent can also play out in drug shortages, Smalley explained.
Referencing the narcotic drug oxycontin, currently in short supply, Smalley commented that “if oxycontin was a big moneymaker, there would be no shortage. There would be some manufacturer out there pulling their hair out to make sure that the product was on the market because they were making a good buck.”
Existing products and those going generic that have very thin margins and do not contribute a lot to the bottom lines of the
companies “wind up having this problem like oxycontin.” There is little financial incentive for industry to resolve the drug shortage issue with these products, the Merck official maintained.
Smalley recounted an experience he had at Wyeth regarding an oral antibiotic that went off patent and the company’s actions at the time that inadvertently led to a shortage of the drug.
“The day the product went off patent,” he explained, “Wyeth did not wait to see what the sales were going to be or how much it was going to earn. They closed the plant, laid everyone off, and began deconstructing the plant, because they knew it was not going to be a big profit contributor.”
Because the generic firms had not yet geared up production and did not anticipate that Wyeth would immediately leave the market, a “significant” shortage situation resulted that lasted “for about six or nine months. That happens a lot.”
Drug shortages are “driving a lot of our compounding right now,” Smalley stressed. “The increasing amount of drug shortages is accelerating the need and demand for compounding.”
Voluntary Outsourcing Registration of ConcernDuring the Q&A after his presentation, Smalley also expressed concern regarding the voluntary approach that has been written into the Drug Quality and Safety Act (DQSA) for pharmacy compounders registering as “outsourcers,” (see IPQ “Monthly Update” Nov./Dec. 2013, pp. 28-30) noting the potential for abuse of the system.
FDA recognizes that some drug availability is going to have to be managed by compounding pharmacies as provided for in DQSA and the follow-up outsourcing registration draft guidance.
In exchange, facilities are supposed to voluntarily enroll so that they can be inspected to assure that they meet relevant CGMP requirements – one of the qualification criteria for the “outsourcer” status. “But the key word is ‘voluntary,’” Smalley said. “So, in the end, who do you think is going to enroll? The ones that really need the help? Or the ones that are in pretty good shape?”
The comment drew a question from a participant, who asked whether a hospital would be more likely to source compounded products from an FDA-registered facility, and whether they would face any liability if there were issues with a product that had been obtained from a compounder that was not registered.
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Smalley responded with an analogy to demonstrate the two facets of the issue: Whether people are aware of registration or accreditation programs, and if so, whether they perceive them to provide any value.
He pointed to USP’s program for accreditation of nutritional supplements. “A manufacturer can enroll in the USP program and get a symbol on their product that says that it meets USP standards for their nutritional product,” he explained. “Maybe it has not been publicized enough, so maybe it is a matter of awareness. But are people willing to pay 20% more to pick a bottle off the shelf that has that label – that so-called seal of approval?”
If someone purchases an electric product in the U.S., Smalley maintained, that person would probably be unwilling to buy a product that did not have an underwriters laboratory label on it. “The fact of the matter is that about 20% of the electrical products in the United States are illegally imported from countries like China, and the UL label has been counterfeited onto that product,” he commented.
While there “should be a willingness to pay a little bit more” to assure product quality, ultimately Smalley suspects that the ability to provide the desired product reliably, in a timely manner, and at a reasonable cost, would be the primary deciding factors for a hospital pharmacy director making sourcing decisions. Whether the firm is enrolled in the FDA program would likely be a secondary consideration.
Smalley also expressed concern that there will be compounders that do not enroll as outsourcers and try to “fly below the radar.”
There are going to be “thresholds” for detection, he commented, such as whether products are introduced into interstate commerce or exceed a certain volume. “There are going to be people out there who are going to say, ‘I understand what that threshold is and I am going to stay below that threshold,’” because of a perception that meeting the FDA requirements would be cost-prohibitive.
“It scares me,” he emphasized, “the whole concept of…having thresholds is just a struggle.”
MERCK’S CHRIS SMALLEY ON DRIVERS FOR INCREASED STERILE COMPOUNDING
At the 2014 PDA annual meeting, Merck BioSterile Validation Engineering Director Chris Smalley reviewed some of the more high-profile contamination events with compounded injectables and then discussed three drivers for the increased reliance of healthcare practitioners on sterile compounding: ● the lack of commer-cially-available products ● drug shortages, and ● cost pressures.
I am going way back before NECC. In 2001, eleven people in Northern California developed bacterial infections from injections with compounded betamethasone – a steroid. Three died.
In 2002, seven people became ill and two died from fungal infections caused by contaminated methylprednisolone, another steroid, made by a compounding pharmacy in South Carolina.
In 2011, contaminated steroids were injected into the eyes of patients in Florida for macular degeneration. There is a product on the market for macular degeneration, but it is extremely expensive. What happens is, the price pressures cause people to consider going to alternate products. There is, in fact, a product that is commercially made, but it does not have as an indication the injection in the eye for macular degeneration. The manufacturer does not make that claim. And compounding pharmacies have arisen that will make that product and will make that claim.
And here, thirteen people, instead of having the macular degeneration stopped – since sometimes you are not curing the macular degeneration but you are stopping the degradation – got a contaminated steroid product that damaged their eyes.
So maybe in 2001, and in 2011, you didn’t hear about it because we have a threshold of how many deaths it takes get our attention nationally. The New England Compounding Center probably hit that threshold with 50 deaths. And what was the product? A steroid injection. And 720 additional people were injured. [Editor’s Note: For more on the compounding problems and the regulatory environment that preceded the NECC crisis, see IPQ’s November 2012 Special Report.]
Okay, 50 deaths probably hit our threshold. Now everyone is interested and everyone is excited. And what you noticed is, every product that we have been talking is a steroid.
What makes this popular? What makes this demand for compounding pharmacies? Physicians do not want to inject a preservative-containing product, intrathecal – into the spinal canal. So what is our root cause?
Lack of Commercially-Available Products
Our root cause is that we are not making commercially available products. There is a need, and the physicians are demanding this from pharmacists. I can tell you, I have been standing in the pharmacy when the pharmacist has said, ‘that’s not commercially available. I can’t give you what you need.’
And of course the pharmacist winds up first telling the nurse, because the nurse is the one who wants the product to give to the patient. The nurse in turn tells the physician. The physician, in turn, calls the pharmacy and dances on the pharmacists face and says, ‘why can’t you give me what I need? I am the captain of this ship.’ Physicians regard themselves as being the captain of the ship. ‘This is what I want. You are responsible as the pharmacist for giving me what I want, for giving me the meds I need to treat my patient. Get it.’ There is a lot of pressure on the pharmacist.
So let’s continue to talk about what drives some of these things…. Sometimes products are commercially available as they are listed in the catalogue, but they are not available at the time the pharmacist needs them.
Drug Shortages
These are recalls from us – the pharmaceutical industry. [In December 2013] Baxter initiates a worldwide voluntary recall of 5% dextrose injection and normal saline solution, 0.9% sodium chloride injection for IV solutions. Okay. A doctor writes an order for a patient. What am I going to do? I am going to take 5% dextrose and I am going to put enough sodium chloride in to get it up to 0.9%. I am going to start compounding, because the product is not commercially available to me.
[Also in December 2013] Hospira issues a voluntary recall of one lot of Lidocaine injection of 2%, 5 ml in 5 ml vials due to the presence of particulate matter. We receive an awful lot of particulate matter recalls. Recently there was a recall where one company found a particle in a vial that was on stability, notified FDA, and wound up recalling the whole lot.
That lot gets recalled. I need Lidocaine 2%. Now I probably have Lidocaine 50% on my shelf. So what am I going to do? I am going to take Lidocaine 50% and dilute it and make up smaller vials. I am now compounding, because commercially available products have been withdrawn from the market. These recalls creating drug shortages are getting to be more and more of a problem….
Drug shortages are driving a lot of our compounding right now. Earlier I talked about how product simply wasn’t commercially available, and now I am talking about how the increasing amount of drug shortages is accelerating the need and demand for compounding.
A Pfizer facility caused a drug shortage…. [There] is an instruction to me as a pharmacist at a hospital from the director of pharmacy to prepare these compounds because these compounds were no longer being made available. The one I want to highlight for you is oxytocin, 10 units in a 500 ml normal saline solution bag. How many people know what oxytocin is normally used for in a hospital? Wow. Didn’t get a lot of hands raised.
It is crucial. If you have a doctor in the delivery room, if you have an OBGYN, and the delivery is scheduled, their hair is going to be on fire if they don’t have oxytocin available. That is the best way I can characterize it.
This is the instruction to the pharmacist: ‘Currently, oxytocin 20 units of 100 and 1000 ml in normal saline solution must still be made in the pharmacy and stocked in the Women’s Care Unit.’ One of the reasons I point this out is because earlier I said that prescriptions are made based upon the physician’s order for a patient. This points out how we are beginning to detach ourselves from that philosophy. Pharmacies in hospitals will compound these and stock them in the nurse’s unit before the doctor’s order has been received, so that when the doctor wants the oxytocin it is there and he can give it to the woman who is going to deliver.
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So we begin to detach ourselves. No one is being evil. No one is being malicious. But philosophically we are beginning to separate the concept of filling to an order. In fact now, even within the hospital, we are compounding to stockpile in anticipation of that order.
So when we talk about these compounding pharmacies not filling to an order – and in fact, this is what FDA has been trying to achieve with the new law – hospitals have been doing this for a while.
Cost Pressures
Cost remains a big concern. Everyone is on a tight budget. The Affordable Care Act (ACA) actually cuts reimbursements further. For those of you who are not familiar with some of the things hospitals are struggling with in the ACA, if someone is admitted to a hospital with one of three types of conditions, such as a heart attack, and they are discharged from the hospital, if they need to be re-admitted to the hospital within a certain time-frame, the hospital will not be paid for the re-admission. The hospital is being told that when it discharges that patient there have to be more effective after-care activities that are taking place to ensure that the patient is not being re-admitted. And by the way, if you need to re-admit the patient, you are not going to be reimbursed for your cost.
The cost demands are extreme on hospitals. I can tell you within the next three years you are probably going to 20% of hospitals in the United States go out of business.
I want to talk more about this third factor. I actually have the article right here. ‘US Medicine’ is a publication that services healthcare providers in the military and also in the Veterans Administration. I continue to receive it, even though I am now retired, as a courtesy.
It talks about how Walter Reed, one of the premier hospitals in the US military system, has saved $700,000. The gist of the article is that by using a closed transfer device, they can now, on average, get ten doses out of nine single dose vials. They know that there is over-filling in single dose vials. So by using a closed transfer system, they now know by the time they open up nine vials, they have enough overfill to that they can get a tenth dose.
They are so proud of it that they published an article. [The pharmaceutical industry is] making single dose vials with the intention that the single dose vial, obviously, will be used one time. Maybe you do it that way because you are able to reduce or eliminate a preservative in that single dose vial. Remember earlier the demand for intrathecal use was ‘let’s get the preservatives out.’ So now you want to use that single dose vial, and nine vials will be combined to give ten doses, and they will save $700,000. It is that important to them. They do not realize the risk that they are putting on the patients.
Between drug shortages, product not-available, plus savings, this is why as an industry we have to be interested in compounding pharmacy.
For a pharmacist, I would tell you, whatever your role is, it is to ultimately meet the needs of the patient. You might regard your customer as being the physician. You might regard your customer as being the healthcare system. But ultimately the needs of the patient need to be met. All of these forces are impacting on what is causing more pharmacy compounding – skills, cost, and availability. But ultimately we have to ensure the patient is not being harmed.
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ICH Q8-11 Oriented Submission and GMP Expectations for Process Validation and Other Quality Issues Taking Shape in Europe
EUROPE
The effort in Europe to update its expectations for process validation (PV) to reflect the quality management principles underpinning ICH Q8-11 moved closer to completion in late February with the issuance of a final guideline on PV submissions for medicinal products and a draft revision of EU GMP Annex 15.
A draft of EMA’s guideline on what should be submitted in marketing dossiers regarding process validation for finished products was put out for public comment in the spring of 2012 (see IPQ “Monthly Update” May 2012, pp. 44-45). The final guideline, modified to reflect the numerous comments received on the draft, becomes effective in August.
Annex 15, which addresses the qualification and validation of processes from a GMP vantage point, was last revised in 2001. A concept paper explaining the motivations for the revision was released by EMA’s GMP/GDP Inspectors Working Group (IWG) in late 2012 (see IPQ “Monthly Update” Jan./Feb 2013, pp. 24-30). Among them are technology advances, changes to the EU GMPs, the incorporation of ICH Q8-11 principles, and the rewrite of the PV drug product submission guidance. Comments on the Annex 15 revision are due by May 31.
A third EMA PV project is focused on biotech active substances (ibid.). A concept paper on the need for a biotech guideline was released for a three-month public consultation in May 2011. Further industry input into the drafting process was gathered at an agency/industry meeting at EMA headquarters in London in mid-2013. Release of a draft for comment is anticipated this year.
The biotech guide, being developed by EMA’s Biologics Working Party (BWP), will instruct assessors and industry on submission expectations in key areas such as: ● clearance of process and product-related impurities, such as host cell proteins and DNA ● column and membrane sanitization and life time ● hold times ● reprocessing ● pooling of intermediates, and ● selection of batches to be included in evaluation and validation batches.
Comments Prompt Revisions in PV Submission Guide
EMA received more than 200 comments from 23 companies and associations on the 2012 draft of its drug product PV submission guideline.
Revised definitions, a new annex on non-standard processes, and a new title were among the changes made to the draft in the wake of the comments.
The comments reflected industry sensitivity to defining process validation and submission requirements in a way that necessitates regulator pre-clearance for any post-approval adjustments – effectively running counter to the continuous improvement mandate in the ICH Q8-10/quality systems paradigm. (Editor’s Note: The stories in IPQ’s Monthly Update for February provide an in-depth review of the problems that manufacturers face in trying to make process and control adjustments, given the limitations, constraints, and disconnects in the current CMC review processes.)
The redefinition of process validation as a “lifecycle” continuum extending from development through post-marketing, as manifested in FDA’s 2011 PV guidance, is an effort to create better alignment with the evolving quality management paradigm (IPQ “Monthly Update” February 2011, pp. 35-41).
In turn, a key focus of the comments on the EMA draft was the perceived divergence from FDA’s guidance – in particular, regarding the concepts of process design, process qualification and continued process verification (see IPQ “Monthly Update” Jan./Feb 2013, pp. 24-30).
“Continuous” is Different than “Continued”
One of the salient aspects of EMA’s drug product PV guideline is its inclusion of the concept of “continuous process verification” as an “alternative approach to traditional process validation, in which manufacturing process performance is continuously monitored and evaluated” using on-line or at-line controls.
EMA describes continuous process verification as applying the principles of ICH Q8 and employing tools such as process analytical technology (PAT), NIR, and multivariate statistical process controls.
While the concept is congruent with the thrust of FDA’s PV guidance, potential terminology concerns do surface when the two documents are juxtaposed.
The FDA guidance does not specifically refer to “continuous process verification,” and would view it as a
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PV enhancement rather than an “alternative” approach. The terminology divergence reflects EMA’s more limited application of the term “process validation” to refer to the stage 2 “qualification” component in FDA’s revised three-stage PV approach.
FDA, in turn, uses the similar term “continued process verification” to designate the third stage in the PV lifecycle – “the ongoing assurance gained during routine productionthat the process remains in a state of control.”
In explaining its response to the comments on the draft, EMA stressed that efforts were made in the final version to harmonize the terminology with FDA.
EMA noted, in particular, that “continued process verifica-tion” is similarly labeled “ongoing process verification” in its guideline, adding that “to avoid confusion between both terms, they have been spelled out in full, and acronyms have been avoided.” On-going process verification, the European agency explained, “is now considered to fall under GMP,” and is addressed in the update to Annex 15.
In response to comments pointing to the differences between its PV guide and FDA’s, EMA explained that its document is aimed at assessors and deals with submission information, whereas the FDA guidance is aimed at industry and inspectors and focuses primarily on GMP considerations. Regarding bringing the two closer together, EMA emphasized that “due to regional regulations, it is not envisaged to align and harmonize approaches between EU and FDA guidelines.”
The concern about the differences may also indicate a need for FDA to more clearly delineate the relationships between the PV lifecycle expectations as defined in its guidance and the related information agency reviewers expect to see in applications.
At issue is where the CMC/review and GMP/inspection boundaries lie and where they intersect, and what role each should play in moving toward a more risk-based, improvement-friendly quality regulatory paradigm.
Non-Standard Processes Clarified
Also drawing industry comment in the EU 2012 draft were the differing submission requirements for “non-standard” processes and how a firm makes a determination of whether a process is non-standard.
In the draft, section eight on “standard vs. non-standard methods of manufacture” stated that, for non-standard processes, “production scale validation data might need to be provided in the marketing authorization application
dossier, unless otherwise justified.” A partial list of non-standard processes was provided, and the onus was placed on the company to make the determination regarding its processes.
The European Federation of Pharmaceutical Industries and Associations (EFPIA) maintained that the list in the draft “may have had merit years ago.” However, “many of the cited examples are now common processes supported by a history of successful manufacture. Some examples include lyophilization, suspensions, modified release, and aseptic processing.”
EFPIA further commented that making a decision whether a process is non-standard is “subjective and could be open to misinterpretation.”
In the final guideline, EMA moved most of the content of section eight into a new Annex II. In the annex, it removed the list EFPIA referred to as outdated, and provided some additional clarification on non-standard process determination.
The annex states, for instance, that all biological products are considered to be non-standard. While the examples of specific manufacturing technologies were deleted, the current draft maintains the same general “categories” of “products or processes which could be considered as nonstandard” as appeared in the draft. These are: ● the manufacture of specialized pharmaceutical dose forms ● the incorporation of some new technology into a conventional process ● highly specialized processes involving new technologies or an established process known, or likely, to be complex and therefore to require particular care, and ● non-standard methods of sterilization.
Regarding PV submission requirements for these categories, the final version changed “might need to be provided” to the more definitive “should be provided.”
The revised section eight in the final guideline focuses specifically on how a firm’s experience with the manufacture of specialized products can be used to justify providing less PV data in a submission.
For specialized products validated using traditional methods, section eight indicates that requests to provide less than full production-scale validation data will be reviewed on a case-by-case basis. A justification that takes into account “the risk to the patient of failure of the product or process” should be provided for each manufacturing site (see box on next page).
A change to the title of the PV submission guideline also resulted from consideration of a comment made to the 2012 draft.
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ISPE commented that the title of the document “be adjusted to more closely reflect its purpose.” It suggested that the “Guideline on Process Validation” be changed to “Guideline on Process Validation Information to be Included in Regulatory Submissions,” which EMA adopted.
Annex 1� Rewrite Reflects QbD
In addition to aligning Annex 15 with the PV guideline and ICH Q8-11 principles, the GMP/GDP IWG noted in its late-2012 concept paper that changes to GMPs since 2001 create the need to update the annex specifically regarding: ● change control ● the implication for product quality reviews ● revisions to Chapters 3 and 5 on dedicated facilities, and ●revisions to Annex 11 on computerized systems.
A comparison of the tables of contents of the 2001 and 2014 versions of the Annex 15 shows where the most updates were made in response to the PV guidance revision and the ICH Q8-11 – specifically, the addition under the “process validation” heading of continuous and ongoing process validation, and new sections focusing on validation of transportation, packaging, utilities, and test methods (see box at right). None of these topics was addressed in the 2001
version. Also noteworthy is the elimination of any mention of retrospective validation.
Also reflected in the Annex 15 revision are updates made to Chapter 1 of the EU GMPs to align with ICH Q10 change management expectations, expanding the “change control” section from two paragraphs to seven. The Chapter 1 revision became effective in January 2013.
The Annex 15 draft now includes more detail regarding change management systems and how they need to be handled as part of the firm’s quality system. Incorporated are the quality-by-design principles of risk management and design space.
The draft notes that “where design space is used, the impact on changes to the design space should be considered against the registered design space within the marketing authorization and the need for any regulatory actions
MHRA Expectations for Data Integrity Self Auditing
The following expectations regarding self in-spections by pharma firms were announced by the UK’s MHRA in December, 2013:
● The MHRA is setting an expectation that pharmaceuti-cal manufacturers, importers and contract laboratories, as part of their self-inspection program, must review the effectiveness of their governance systems to ensure data integrity and traceability.
● This aspect will be covered during inspections from thestart of 2014, when reviewing the adequacy of self in-spection programs in accordance with Chapter 9 of EU GMP.
● It is also expected that in addition to having their owngovernance systems, companies outsourcing activities should verify the adequacy of comparable systems at the contract acceptor.
● MHRA invites companies that identify data integrityissues to contact them by email at: [email protected]
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assessed.”
The changes that the IWG made to Annex 15 regarding the implications for product quality reviews and the changes related to Chapters 3 and 5 and Annex 11 were minimal.
The draft notes that ongoing process verification should be used to support the validated status of the product in the product quality review, along with a reminder that “incremental changes over time should also be considered and the need for any additional actions (e.g. enhanced sampling) should be assessed.
The use of dedicated equipment is recommended when cleaning validation has shown to be ineffective or is not appropriate.
Regarding computerized systems, Annex 15 points to Annex 11: “Computerized systems used for the manufacture of medicinal products should be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q10 and Q11 should also be taken into account.”
Other EU GMP Chapters Under Revision
EMA is working on revising several other chapters and annexes of the EU GMPs. These revisions will clarify the expectations regarding current compliance focal points, such as supply chain oversight, shared facilities, starting materials, lab method transfers, and investigating and reporting quality defects (see IPQ “Monthly Update” Jan./Feb 2013, pp. 31-41).
In early 2013, EMA released draft revisions of four of its GMP chapters for a six-month consultation period: ● Chapter 3, “Premises and Equipment” ● Chapter 5, “Production” ● Chapter 6, “QualityControl,” and ● Chapter 8, “Complaints, Quality Defects and Product Recalls.”
EMA noted that the revised Chapters 3 and 5 should be read in conjunction with a draft EMA guideline on “setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities,” which was released just prior to the chapter revisions.
Chapters 3, 5, 6, and 8 are slated to be finalized in 2014, according to the GMP/GDP Inspectors Working Group (IWG) work plan. Specifically, Chapter 6 will now include identification of minimal requirements for the transfer of analytical methods, and Chapter 8 will incorporate requirements for product shortage notifications and introduce specific quality risk management concepts within
the context of the complaints and recalls chapter.
A revision of Chapter 2 on personnel came into effect in February, 2014. The chapter was amended to incorporate the senior management responsibilities described in ICH Q10.
Also emerging from the EMA GMP pipeline in November 2012 was a concept paper proposing the revision of Annex 17 on parametric release. A redraft of the Annex is expected in 2014.
Sterile Product and QP Annexes Also in Focus
Annex 1 on the manufacture of sterile products and Annex 16 on the qualified person (QP) and batch release are two other current EU GMP focal points.
The 2008 revision of Annex 1 proved controversial when it was issued and industry concerns about the revision have continued. (Editor’s Note: The Jan./Feb. 2009 issue of IPQ provides an extended analysis of: ● the changes made to Annex 1 by the rewrite ● the concerns regarding its interpretation andimplementation, and ● the broader implications for aseptic processing regulation.)
The EMA GMP IWG has been considering whether to again revise the annex or address the concerns through Q&As (see IPQ “Monthly Update” Jan./Feb 2013, pp. 31-41).
The discussions on the best way to move forward on Annex 1 were essentially tabled with the bolus of work the IWG faced in the wake of the Falsified Medicines Directive (FMD). However, Annex 1 is included on the agenda in the IWG’s work plan for 2014. It calls for the IWG to work with PIC/S to arrive at “the best approach to dealing with recurring issues on the interpretation of this annex and whether guidance is needed on biofilms.”
The EU GMPs form the basis for PIC/S GMPs, and the international pharmaceutical inspection group is actively involved in EMA GMP modification discussions accordingly. With its expert circle on sterile products, PIC/S will provide important input into the Annex 1 debate.
A concept paper on revising Annex 16 was issued by the IWG in 2011 (see IPQ “Monthly Update” June 2011, pp. 9-19). A revision of the annex, reflecting the concept paper and the ensuing comments and discussions around it, was released for public comment in July 2013 (see IPQ “Monthly Update” July/August 2013, pp. 22-30).
Drivers for the revision were identified by the EMA as including: ● the globalization of the supply chain, which is putting more distance between QPs and the manufacturing
operations for which they are ultimately responsible ● the introduction of new quality control strategies such as real-time release ● the implications of the FMD and the refining of the GDPs in Europe ● the principles embedded in ICH Q8-10 ● a new manufacturing and import authorization (MIA) interpretation document, and ● differences between member states in interpreting the existing Annex 16.
Among the significant changes EMA incorporated into the 2013 revision were a clearer distinction between the release of a batch and its certification by the QP, directions for what responsibilities the QP can share and how, and a template for use by a QP to sign off on a subset of manufacturing steps.
The comments that came in on the revision have been reviewed by the IWG and a revision is being drafted, with a release anticipated in 2014.
In its 17-page comment letter, EFPIA expressed appreciation for the efforts made in revising the annex to foster harmonization of the requirements and their interpretations throughout the EU. However, the association cautioned that more attention would be needed to assure that those objectives are achieved.
EFPIA’s concern was “specifically relevant to duties that have to be performed by a QP and those that can be delegated.” The association stressed that “allowing the QP to rely on the company or site-based pharmaceutical quality systems as given in ICH Q10 is a key aspect to ensure that requirements laid down in this annex are being fulfilled.”
Europe’s QP Association joined EFPIA in expressing concern with the practical implementation of some of the provisions and terminology in the revised draft.
IWG has Full Agenda for �01�
EMA’s GMP/GDP IWG includes senior representatives from the inspectorate of the European Economic Area member states and the European Commission (EC), along with observers from EDQM, the inspectorates of the countries accessing to the EU, and MRA partner countries. Under the group’s purview are GMP and GDP inspection procedures and guidance, MRAs, legislation impacting GMP inspection activity, and inspection harmonization.
Also prominent on the IWG agenda for 2014 is continued work on developing procedures and coordinating inspections related to centrally authorized products and to master files for plasma and vaccine antigens.
The plan calls for EMA to “build upon its commitment to making best use of EU inspection resources by leveraging information from international regulatory authority partners
wherever possible.”
Other aspects of the international component of the IWG responsibilities are also targeted for attention, including simplifying all operational aspects of the EU mutual recognition agreements and encouraging the use by MRA partners of the EudraGMDP database to replace the paper exchange of GMP certificates. Specifically targeted are managing the Health Canada audits of new EU member states, and extending the scope of the MRA with Japan.
The IWG will continue its dialogue with EDQM, WHO, PIC/S, and other international regulators – paying particular attention “to supporting collaborative activities aimed at optimizing the use of inspection resources and capacity building…through existing international platforms.”
Similarly to the workload facing FDA’s drug compliance office in implementing the FDA Safety and Innovation Act (FDASIA) and the Drug Quality and Security Act (DQSA) (see IPQ “Monthly Update” January 2014, pp. 13-20), the EMA IWG will have its plate full in implementing the EU Falsified Medicines Directive (FMD) (see IPQ “Monthly Update” July/August 2013, pp. 16-21).
Included under the FMD umbrella are refining the procedures for coordinating third country inspections and dealing with serious GDP non-compliance. Other FMD topics that will be receiving attention are the GMP and GDP principles and guidelines for active substances, and finalizing the risk assessment guideline regarding excipient GMPs.
The IWG will continue its focus on the implementation of the rules for API importation under the directive and the effort to avoid product shortages when written confirmations are not available from exporting third country authorities (ibid.). The plan also calls for IWG involvement in implementing an “improved procedure for managing GMP non-compliance linking to processes under development to manage shortages.”
EMA’s recent description of the IWG explains that there is increasing awareness of the importance of interactions between GMP inspectors and assessors.
IWG meets with the Quality Working Party at least once a year, and contributes along with the QWP and Biologics Working Party (BWP) to EMA’s PAT team. Among the joint projects with the QWP was a workshop on QbD held at the end of January in London, which was coordinated by PDA Europe.
The IWG and QWP will be working with EDQM on issues related to reverse osmosis for production of water for
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injection (WFI) and to biological indicators for monitoring/control of sterilization.
QWP’s �01� CMC Plate Also Full
The Quality Working Party is set up to: ● advise and support EMA’s committees for human and veterinary medicinal products (CHMP/CVMP) on the broad range of issues related to the CMC component of the review process ● develop relevant harmonized standards and guidance, and ● liaise with other EU groups involved with or impacted byquality regulation and with international organizations and agencies.
On the QWP radar screen are training of quality assessors, and industry workshops. The agenda includes working with the EU PAT team on new CMC approaches and with EDQM on European Pharmacopeia monographs and general methods, terminology, certification, and impurities.
The QWP will be helping in implementing ICH M7 on genotoxic impurities and Q3D on metal impurities. It will also be participating in the ICH discussions on the common technical document (M4), and developing a Veterinary ICH (VICH) guideline on bioequivalence and revising GL3 on veterinary API and product stability testing.
QWP’s collaborative projects with EDQM during 2014 will include reviewing the existing qualification and limits of impurities on approved medicinal products in the EU and their presentation in the EP general chapters and monographs.
DOWNLOADS FROM THE STORY:
• Comments on Annex 1�• EMA GMP/GDP IWG �01� work plan• EMA QWP �01� work plan
EMA’S �01� CMC AND GMP REGULATORY GUIDANCE WORK PLANS
The following are the guidance efforts that the EMA’s GMP/GDP Inspectors Working Group (IWG) and the CHMP/CVMP Quality Working Party (QWP) have on their respective agendas in 2014. In the IWG section, the documents being worked on are followed by a brief description of the work plan goals. The QWP guidance initiatives pertain to human (“H”) and/or veterinary (“V”) medicinal products as indicated.
GMP/GDP Inspectors Working Group
● EU GMP guide:
Chapters 3 and 5 (premises and equipment and production): To finalize all changes planned for these chapters.
Chapter 6 (quality control): To finalize the revision aimed at identifying minimal requirements for the transfer of analytical methods.
Chapter 8 (complaints and product recall): To finalize the revision dealing with product shortage notifications and to introduce specific quality risk management concepts within the context of this chapter.
Annex 1: To agree, in consultation with PIC/S, on the best approach to dealing with recurring issues on the interpretation of this annex and whether guidance is needed on biofilms.
Annex 15 (validation): To finalize the revision to update guidance including any necessary changes to maintain consistency with the new CHMP guideline on process validation in the light of ICH Q8, Q9, Q10.
Annex 16 (certification by a QP and batch release): To finalize the revision aimed at updating this annex.
Annex 17 (parametric release): To finalize the revision aimed at updating this annex.
● Importation of medicinal products: To consider the need for specific guidance for importers
● EudraGMDP database: To continue to fulfil the role of Telematics Implementation Group (TIG) for EudraGMDPand to act upon the recommendations of the EudraGMDP IT subgroup formed to advise the TIG. To examine ways that the planning module can be used as a common tool for international collaboration.
Finalize the guideline on GDP principles for active substances
Finalize the risk assessment guideline to establish appropriate GMPs for excipients
Revise the procedure for coordination of third country inspections
Finalize the procedure for dealing with serious GDP non-compliance
CHMP/CVMP Quality Working Party
● New technologies and approaches to quality as described in ICH guidelines Q8 (pharmaceutical development),Q9 (quality risk management), Q10 (pharmaceutical quality systems) and Q11 (development and manufacture of drug substances):
Guidelines on the manufacture of the finished dosage form (CPMP/QWP/848/96 & EMEA/CVMP/126/95): revision (H/V)
Guidelines on the chemistry of new active substances (CPMP/QWP/130/96-Rev1 & EMEA/CVMP/541/03): revision (H/V)
Guideline on the chemistry of active substances (3AQ5a/1987): revision (H/V)
Guidance document on definition of starting materials (H/V)
Q & A document on QbD pilot (H/V)
● Guidance on genotoxic impurities in veterinary medicinal products (multidisciplinary topic led by SWP):contribution to the development (V)
● Work on the development of an EU harmonized approach to application of quality risk management to theassessment of applications (H/V)
● Guideline on stability testing for applications for variations to a marketing authorization: finalize revision (H/V)
● Reflection paper on definition of new active substances (H)
● Reflection paper on the assessment of the quality of medicinal products containing existing/known activesubstances: revision (H/V)
● Reflection paper on the use of co-crystals and other solid state forms of active substances in other medicinalproducts (H/V)
● Guidance on the quality aspects of biowaivers (H/V)
● Reflection paper on quality aspects of medicines for older people (H)
● Guidance on packaging (H/V)
● Guideline on quality and bio-equivalence of topical products (H)
● Update, operation and maintenance of the QWP quality database, accessible to all quality assessors in themember states, where harmonized decisions taken at QWP meetings are recorded (H/V)
● Update, operation and maintenance of the QWP core team database, accessible to all quality assessors in themember states, where decisions taken at QWP core team virtual meetings are recorded (H/V)
● Review of applicability and adaptation of CPMP/CHMP guidelines to veterinary medicinal products (V)
● Review of validity of existing human and veterinary quality guidelines and other QWP guidance documents (H/V)
MONTHLY UPDATE - MARCH/APRIL 2014
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Updates in Brief
CMC/REVIEW
FDA Requests Comments on NDA/ANDA Processes
In late March, FDA put out a Federal Register announcement requesting public comment on its drug application processes that could open the door for industry input on the CMC issues involved in expedited reviews and post-approval changes (see IPQ Monthly Update February 2014). The agency is looking for potential simplifications or modifications that would make the review process more efficient. Comments are due by May 23, 2014.
The Global Ingredient Archival System (GinAS) Progressing
A progress report on the “Global Ingredient Archival System” (GinAS) will be presented at the IPEC/ExcipientFest conference in late April. The system is being developed through cooperation between NIH, FDA, and industry with the intent to “provide a consistent definition of substances globally, and a common identifier for all the substances used in marketed medicinal products as well as active substances under clinical investigation.”
FDA Issues New BA/BE Draft Guidance
An FDA draft guidance for establishing bioavailability/bioequivalence (BA/BE) was released in late March and is intended to replace the existing 2003 BA/BE guidance. The guidance details the methods most suitable and accurate for the determination of BA/BE, as required by FDA. An expanded section is included on in vitro studies and their applicability for different formulations. Changes also include subsections on combination drug/device products, endogenous substances, and advice on excipients that affect BA/BE.
FDA Releases Draft Guidance on Vial Overfills
FDA released a draft guidance in mid-March to better define acceptable practices regarding the overfilling of vials. The guidance, open for comment until June 12, illustrates the best use of overfilling to achieve accurate doses, while preventing contamination.
FDA Finalizes Guidance on Interpreting Sameness of MAbs Under Orphan Drug Regs
In late April, FDA released a guideline on how to interpret “sameness” in the molecular structure of MAb products, antibody conjugates, fusion protein products, and bio-specific antibodies. The guideline was released as a draft in 1999 in response to the related language used in the 1992 orphan drug regulations. The final version remains similar in structure and wording with the exception of reference to the Biologics Price Competition and Innovation Act of 2009.
GMP/INSPECTION
ISPE Launches Quality Metrics Pilot Program
ISPE announced in mid-March that it will conduct the industry’s first “Quality Metrics Pilot Program” designed to define standard metrics reporting to FDA. The pilot will test a series of indicators that support an FDA risk-based inspection program. ISPE plans to launch the pilot with workshops for industry education and input, involving FDA participation, during the 3rd Annual ISPE-FDA CGMP Conference in Baltimore, MD, in early June 2014. The pilot will be open to a limited number of sites and product types, and will represent branded, generic, and over-the-counter products, ensuring statistically meaningful findings.
CDER Seeks Mapping Capabilities
In mid-March, FDA issued a solicitation for software to aid in geo-spatial mapping data analysis. According to the FDA Statement of Work, “the focus [of the] pharmaceutical quality platform is to geo-map the facilities that manufacture drug products in case of issues, to ensure the stability and quality of supply chain.” By being able to map all facilities that manufacture drug products, FDA will be able to quickly locate trouble spots and deploy resources.
EMA announced in mid-March that it will launch a fast-track for drug approval termed the “adaptive licensing pilot project.” Like FDAs breakthrough therapy pathway (see IPQ “Monthly Update” September 2013, pp. 2-23), the program is intended to grant early access for medicines meant to treat unmet needs. Companies who are interested in participating in the pilot are re-quested to submit ongoing drug development programs for consideration.
EMA Concept Paper Proposes a Guideline for the Selection of Sterilization Processes
In early April, EMA released a concept paper on developing a guideline for the selection of sterilization procedures that would align EMA’s advice with ICH Q8. The period for public consultation lasts until July 9, 2014.
EMA Finalizes Guideline on Stability Requirements for Variations
In mid-March, EMA published a revision to its 2005 guideline on stability testing for changes made to a marketing authorization. The revision provides specific indications for a variety of Type II variations previously unaddressed. It clarifies that three months of stability data is required for products known to be stable. For products known to be unstable or if there are changes to the qual-ity characteristics of the active substance, the requirements increase to six months of data. The guideline also requires six months of stability data following changes made to: • excipients that may impact quality • dosage forms • batch size, or • fill volume.
UK Begins Construction on Biologics Research Center
The groundbreaking of the National Biologics Manufacturing Centre in the UK took place in mid-April with completion esti-mated for 2015. The UK government is putting 38 mill. pounds into the NBMC to facilitate innovation in the field of biologics and to help strengthen the UK’s bio-pharma sector by reducing risks for companies involved in developing new biologic products.
MHRA Releases 2014-2015 Business Plan
The MHRA has released their business plan for 2014-2015 as of mid-April. The “key strategic activities” section of the plan shows an emphasis on surveillance as well as on increasing collaboration with other regulators to better ensure the quality of medicinal products.
EC Reports on Advanced Therapy Regulatory Uncertainties
In late March, the EC published a report about currently unaddressed issues for “advanced therapy medicinal products(ATMP),” such as gene therapy or tissue engineering. Of concern in the report is that only four ATMPs have been approved in Europe, de-spite numerous applications, and that different member states have come to different conclusions regarding the same ATMPs.
EMA Q&A Addresses Post-Authorization
In early April, EMA released the first installment of a Q&A intended to provide an overview of EMAs position on issues typically discussed with marketing authorisation holders regarding post-authorization procedures. The Q&A is a running list and will be updated as new questions and answers emerge.
EDQM Clarifies CEP Evaluation Policy
In late March, EDQM clarified its approach to assessing new applications for CEPs. The policy document explains that the process is handled in two rounds: • the evaluation of the original application, and • if necessary, the evaluation of additional informa-tion upon request from EDQM. Following these two rounds, an application lacking the necessary data or response will be closed, though the application may be resubmitted.updated as new questions and answers emerge.
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INTERNATIONAL
CMC/REVIEW
Brazil to Require Notice One Year Prior to Drug Withdrawal
A new mandate, approved by Brazil’s Anvisa in late March, requires drug manufacturers to provide a year’s notice prior to removing a drug from the market if that withdrawal could lead to a shortage. If the withdrawal would not pose a risk of a shortage, the notice can be given six months ahead rather than twelve. Additionally, there is a 72-hour requirement of notice if sudden, previously unforeseen circumstances could lead to a drug shortage.
EDQM Launches Anti-Counterfeiting Database
In late March, as part of its anti-counterfeiting activities, EDQM announced the launch of a new database called “Know-X.” The database collates reports on counterfeit/falsified medical products that have been detected in European member states, and also contains details on closed cases of counterfeit/falsified medical products, technical information on the testing performed, the authorities involved, and what actions were taken. The information provided is gathered from various sources and is intended to provide governments with decision aids for the management and prevention of specific risks.
EMA Revising Applications/Advice Procedures
In late March, EMA announced a revision to its procedures for application submission and for advice requests that reflects a structural reorganization in September 2013. The changes, one of which relates to the EMA contact persons, will be implement-ed for new applications submitted as of April 1, 2014. For ongoing applications a transition plan has been put into place.
EMA Issues Concept Paper for Revised Immunogenicity Guideline
EMA issued a concept paper in late February revising its immunogenicity assessment guideline. The aim of the revision is to clarify how immunogenicity data is presented, to introduce a risk-based approach, and to determine the appropriate studies needed for different products. [For a discussion of the quality/immunogenicity relationship, see IPQ “Monthly Update” Janu-ary 2014, pp. 21-31.]
GMP/INSPECTION
EC Publishes Q&A on GDPs
In late March, the European Commission published a “question and answers” (Q&A) related to its new guideline on Good Distribution Practice for medicinal products for human use, which went into effect in November 2013. The document contains 25 Q&As. The questions focus on: ● competence and training of personnel ● segregation of products ● temperature and environmental control ● alarms and deviations ● qualification of customers ● verification of authorization for sale ● control of returned products and recall procedure, and ● transport requirements, such as temperature and safety.
EC Revises EU GMP Chapter 6 on Quality Systems
In late March, the European Commission published a revision of Chapter 6 of the EU GMPs, which covers quality control. The revision includes a new section on analytical methods transfer that calls for verifying application conformance and having a transfer protocol. Other revisions involve: ● investigating OOS trends ● establishing a risk-based sampling plan ● culture media and strains management, and ● sample management. [See story p. 50 for more on EU GMP revision initiatives.]
In a statement published in early April, EMA announced its collaboration with TGA on creating better access to orphan drugs. In the statement, EMA noted that “the two regulators have agreed to share the full assessment reports related to marketing authorisations of orphan medicines.” The statement goes on to note that this strengthens pre-exisiting collaborations, such as those involved in GMPs.
GMP/INSPECTION
FDA and EMA Extend QbD Pilot, Plan More QbD Guidance
In early March, FDA and EMA announced a two year extension of their pilot program for collaborative review of QbD applications launched in 2011. FDA and EMA also indicated that additional QbD guidances are expected to be published in 2014. [See story on p. 50 for more on EMA’s 2014 quality initiatives.]
WHO Revising its Guideline on “Hold Time”
In late February, WHO published a revised draft of its guideline on best practices to follow when designing hold time studies. The new draft adds the recommendation that manufacturers consider using a “most probable” rather than a “worst case approach” to hold times.
