VOLUME: 21 - ISSUE: DEC 2015 |

PHARMA UPTODAY

PHARMA UPTODAY

2

Inside this issue

3 News Uptoday 15 New Guidance 21 Audit Findings 483 Observations

- Diabetes Corporation of America - Pine Pharmaceuticals

23 Warning Letters

- Warning letter: American Family Pharmacy - Warning letter: Dr. Reddy's Laboratories Limited - Warning letter: Sandoz Private Limited

32 Article of the Month

- Data Integrity Checklist related to Electronic Records and Electronic Signatures.

33 Regulations of the Month

- Sec. 211.46 Ventilation, air filtration, air heating and cooling - Sec. 211.48 Plumbing

PHARMA UPTODAY

3

News Uptoday

General Information on CDER Small Business and Industry Assistance (CDER SBIA)

Although large corporations produce many of the products that FDA regulates, smaller businesses

actually constitute a large majority of Center for Drug Evaluation and Research (CDER) regulated

companies. Such small businesses provide a vast array of the drug products available to American

consumers.

What is a small business?

The definition of a small business used by the CDER Small Business and Industry Assistance

(CDER SBIA) Program is based on two statutes: Safe Medical Devices Act of 1990 and the Small

Business Innovation Development Act of 1982. Both statutes specify that a small business is defined

as having no more than 500 employees, including affiliates. An affiliate is defined as a business

entity that has a relationship with a second business entity if one business entity controls, or has the

power to control, the other business entity, or a third party controls, or has the power to control, both

entities.

By definition, small businesses lack many of the resources available to larger pharmaceutical

companies. In addition to having a limited number of employees, they are often engaged in the

development of their first product. As such, they may have minimal to no experience with the laws

and regulations governing drug development in the United States.

How is CDER organized to help regulated small pharmaceutical businesses?

Because FDA has long recognized the unique needs of small business, a network of FDA

offices exists in the Commissioner's Office, in the regional offices, and in the product-specific

Centers to help small businesses understand the Agency's structures and rules. In the

Commissioner's Office, the Office of Ombudsman has responsibility for liaison with the Small

Business National Ombudsman for resolving complaints against the Agency brought by small

business owners. Also in the Commissioner's Office, the Economics Staff works with the Centers to

assure that the impacts of all regulatory burdens on small businesses are considered, and that

adverse impacts are lessened whenever possible, before regulations are issued.

In CDER, the Office of Communications includes a small business staff that answers inquiries from

small business owners, conducts outreach efforts, and participates in programs on emerging topics

of interest to small business.

Each of FDA's five Regional Offices has a Small Business Representative (SBR) to provide outreach

and training to, and answer specific inquiries from, small businesses across the country. FDA

PHARMA UPTODAY

4

Regional Offices have answered thousands of questions, conducted scores of training programs,

and organized more than 50 "grassroots" meetings in the last few years to educate industry,

particularly small business, about emerging regulatory topics of interest. In addition, grassroots

meeting are regularly conducted by the FDA Centers to elicit input on proposed regulations.

In addition to providing ready access to FDA personnel who are knowledgeable about the concerns

of small business, FDA provides a wealth of written and electronic information of importance to small

business.

In developing its regulatory policies and programs, FDA strives, whenever possible, to moderate

adverse impacts on small business. The Agency has received some 45 Vice-presidential "Hammer

Awards" for regulatory improvements, virtually all of which directly benefit FDA's small regulated

businesses.

What is the purpose of the CDER Small Business and Industry Assistance (CDER SBIA)

website?

The purpose of this website is to assist small businesses with timely and accurate information on

CDER's (Center for Drug Evaluation and Research) programs and services; organizational and

contact information; and links to FDA laws, regulations and guidances that affect small business.

Information is also provided on financial assistance and incentives that are available for drug

development. For small business inquiries, contact Brenda Stodart, Pharm.D. at 301-796-6707

or CDERSBIA@fda.hhs.gov.

Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm053

133.htm

Pfizer, Allergan Confirm Preliminary Merger Talks

Pfizer is in preliminary talks to purchase part or all of Irish drugmaker Allergan, the two companies

confirmed last week.

News of the talks comes seven months after Allergan — which is best known as the maker of Botox

(botulinum toxin) — was purchased by Actavis in a deal valued at roughly $70 billion. Actavis

subsequently changed its name to Allergan.

Pfizer Partners With GSK to Develop PCMM Prototype

Pfizer has entered into a multi-year partnership with GlaxoSmithKline to build on former’s existing

portable, continuous, miniature and modular prototype for oral solid dose pharmaceutical

development and manufacturing. The prototype is an autonomous and transportable pod that

accelerates the speed of tablet production.

PHARMA UPTODAY

5

Under the deal, the two companies will create the next-generation design of Pfizer’s current PCMM

prototype. Financial terms of the deal were not disclosed.

Pfizer spokesman Dean Mastrojohn says the initial phase of the collaboration will focus on the

miniaturization of the oral solid dose processing equipment, enabling it to be deployed in a

significantly smaller POD — a portable, autonomous space — and more existing facility spaces.

He adds that the companies will conduct design work needed to add continuous film coating and

encapsulation to the prototype.

Mylan Receives U.S. FTC Clearance for Proposed Acquisition of Perrigo and Confirms

Governance Changes for the Combined Mylan-Perrigo Company

Mylan N.V. (NASDAQ: MYL) today announced the U.S. Federal Trade Commission ("FTC") has

cleared the company's proposed transaction to acquire Perrigo Company plc (NYSE: PRGO; TASE)

subject to Mylan's divestiture of certain products following the consummation of the offer. The FTC

clearance represents the final regulatory clearance needed by Mylan to close its acquisition of

Perrigo and represents the last remaining condition that needs to be satisfied for the successful

completion of the offer other than the acceptance condition.

Mylan's Executive Chairman Robert J. Coury commented, "We are delighted to have received FTC

clearance, making our offer for Perrigo now unconditional other than the one final step, which now

rests solely in the hands of Perrigo shareholders. We are very confident that Perrigo shareholders

will support this transaction by tendering their shares by 8:00 am ET on Nov. 13, 2015."

"In this regard, following the successful completion of our acquisition of Perrigo, and consistent with

my comments during our Q3 Earnings Call last Friday and our previously announced steps to cancel

the Mylan preferred shares issued to the stichting, Mylan will submit changes to corporate

governance for a vote by shareholders of the combined Mylan-Perrigo entity at our next annual

general meeting, including proposals regarding whether or not to retain the stichting structure as well

as the process for nomination and election of directors."

Under the terms of Mylan's offer, Perrigo shareholders will receive $75 in cash and 2.3 Mylan

ordinary shares for each Perrigo ordinary share. On September 14, 2015 Mylan officially

commenced its formal offer to acquire all outstanding ordinary shares of Perrigo.

The offer is being made in accordance with Mylan's announcement (dated April 24, 2015 and

amended on April 29, 2015 and on August 13, 2015) pursuant to Rule 2.5 of Irish Takeover Rules

that set forth Mylan's legally binding commitment to commence an offer and the Offer to Exchange /

Prospectus (being the offer document for the purposes of the Irish Takeover Rules)

dated September 14, 2015. The offer and withdrawal rights are scheduled to expire at 1:00

PHARMA UPTODAY

6

P.M. (Irish time)/8:00 A.M. (New York City time) on November 13, 2015, unless the offer is extended

with the consent of the Irish Takeover Panel. The acceptance condition for the offer requires greater

than 50% of Perrigo ordinary shares to have been tendered into the offer.

A copy of the Offer to Exchange/Prospectus and other related materials have been mailed to Perrigo

shareholders and the Offer to Exchange/Prospectus is available at perrigotransaction.mylan.com.

Source: http://newsroom.mylan.com/2015-11-03-Mylan-Receives-U-S-FTC-Clearance-for-Proposed-

Acquisition-of-Perrigo-and-Confirms-Governance-Changes-for-the-Combined-Mylan-Perrigo-

Company

Medicinal Products stolen from Distribution Warehouses - an Increasing Risk

One of the main reasons for the revision of the EU GDP Guideline in November 2013 was securing

the so-called supply chain from falsified medicinal products. Indeed, there has been in many

countries (like in South America but also in the USA) an increasing number of cases where large

quantities of medicinal products have been robbed to be then partly marketed with counterfeited

contents. Because of their original packaging materials, it is hard to recognize such counterfeits.

The EU GDP Guideline therefore requires in section 3.2. Premises that:

"Unauthorised access to all areas of the authorised premises should be prevented. Prevention

measures would usually include a monitored intruder alarm system and appropriate access control.

Visitors should be accompanied."

In addition, section 5.2. Qualification of suppliers sets strong requirements which should prevent

medicinal products from illegal sources from entering the legal supply chain. It states:

"Where medicinal products are obtained from another wholesale distributor, the receiving wholesale

distributor, must verify that the supplier complies with the principles and guidelines of good

distribution practices and that they hold an authorisation for example by using the Union database. If

the medicinal product is obtained through brokering, the wholesale distributor must verify that the

broker is registered and complies with the requirements in Chapter 10 ( 1 )."

A current case shows how important this new regulation is. The Drug Commission of German

Pharmacists (AMK - Arzneimittelkommission) is informing that diverse medicinal products from CSL

Behring and Pfizer have been stolen at the logistics service provider Thermomed GmbH. According

to the AMK news, pharmacies are asked to be particularly aware as it can't be excluded that there

may be an attempt to bring illegally the stolen medicinal products (including refrigerated products)

into the supply chain. In this context, medicinal products should be basically purchased from

authorised pharmaceutical wholesalers only.

PHARMA UPTODAY

7

The problem of falsified medicinal products entering the legal supply chain through stolen goods has

long since arrived in Europe as you can see in HIV medicinal product case Viread (Tenofovir) in

Germany and the theft of Herceptin in Italy. The case in Italy caused spectacular headlines as many

attempts were taken by counterfeiters to bring manipulated Herceptin into the legal supply chain.

India and the UK establish a strategic partnership in healthcare

King’s College Hospital has become the strategic clinical partner for the first Indo UK Institute of

Health in New Chandigarh.

Backed by up to £100 million of private investment, the project is the first of a proposed 11 Indo UK

Institutes of Health which will see high quality hospitals, nursing schools and medical colleges

developed across India. When fully implemented, the initiative will amount to a £1 billion investment

into India’s healthcare system.

The UK and Indian governments have set up an implementation taskforce to ensure closer

collaboration and speedy implementation of these and other healthcare projects. These aim to bring

the UK’s finest universities, companies and NHS organisations to India.

Healthcare UK assisted Kings College Hospital and Indo UK Healthcare Pvt Ltd to bring this exciting

partnership to fruition. It will continue to support the development of the Indo-UK Institutes of Health.

George Freeman MP, Minister for Life Sciences welcomed the announcement which was made

during Prime Minister Modi’s visit to the UK from 12th to 13th November 2015.

It’s great news that King’s College Hospital NHS Foundation Trust has agreed to be the strategic

clinical partner for the first Indo UK Institute for Health in New Chandigarh. This £100 million

collaboration, a world first, is a sign of the huge global export market for the UK healthcare and life

sciences sector.

I would encourage other UK companies, academic institutions and NHSorganisations to work with

Healthcare UK to engage in the Indo UK Institutes for Health project. As one of the fastest

developing economies in the world, with over 1 billion people, India is fast becoming a vast market

for UK health services and technology.

Source: https://www.gov.uk/government/news/india-and-the-uk-establish-a-strategic-partnership-in-

healthcare

PHARMA UPTODAY

8

Top 20 generics companies by 2014 revenue

To most of the world, the term "generic" suggests something everyday, common or bland, but to the

drug industry generic is anything but bland. It represents a high-volume, low-margin business that is

certainly not for sissies.

It calls for scientific and manufacturing skills, a superb sales operation, and fortitude. It comes with

risks but also has plenty of rewards. In the U.S., the largest drug market in the world, generic drugs

account for 80% of the prescriptions written. According to data from the market intelligence miners

at EvaluatePharma, worldwide sales of generic drugs in 2014 were $74.2 billion, up 7% for the year.

Of that, the top 20 generics producers collected $61.7 billion, 83.1% of the take.

But the fact is, most of those 20 hold only a fraction of the whole. Only the top two generics

companies, Teva Pharmaceuticals ($TEVA) and Novartis ($NVS), which sells generics through

its Sandoz operation, hold double-digit shares, 12.2% and 11.5% respectively. Only the top 5

generics companies, which in 2014 also included Mylan ($MYL), Actavis and Sun Pharmaceutical,

held a market share above 5%. To dice it another way, those top 5 had 2014 generics sales of $35.2

billion, 47.4% of the worldwide generics sales and 57% of the sales generated by the top 20. You get

the picture.

Still, when you look at the tail end of the spectrum, even number 20, Japan-basedNichi-Iko

Pharmaceutical, had generics sales of $1.2 billion.

The current year may be remembered for awhile, with a lot of M&A germinating, some of it friendly,

some not so friendly. Teva has a $40-plus-billion deal to buy essentially Actavis, the generics

business of Allergan ($AGN), which has decided to trade in its generics heritage to concentrate on

the branded side of the ledger. That deal will elevate Teva's leading position so that it should be

unreachable in size for some time. Meanwhile, Mylan is trying rather awkwardly to pull off a buyout

of Perrigo ($PRGO), which Perrigo is working hard to avoid.

It is worth noting that there was some significant M&A action in generics in 2014, like Mylan's $5.7

billion deal to buy Abbott Laboratories' ($ABT) generics business in developed countries and Sun

Pharmaceutical's $4 billion takeover of troubled Indian compatriot Ranbaxy Laboratories.

Other notable events in 2014 exemplify some of the challenges of the generics business. High drug

prices have become the topic du jour recently, but last year a number of generics players said

employees had been subpoenaed by federal prosecutors to give up information on potential

collusion on pricing. Impax Laboratories ($IPXL) and Lannett both acknowledged in 2014 that

employees in their operations had received DOJ subpoenas seeking info on generic drug pricing.

All of this adds up to a piece of the pharma industry that is steady and profitable, and not at all bland.

Take a careful read through this report and let any of the 5 editors who contributed to it know what

you think.

PHARMA UPTODAY

9

1. Teva

2. Novartis - Sandoz

3. Allergan

4. Mylan

5. Sun Pharmaceutical

6. Aspen

7. Hospira

8. Sanofi

9. Fresenius Kabi

10. Lupin

11. Dr. Reddy's Laboratories

12. Apotex

13. Stada Arzneimittel

14. Aurobindo

15. Cipla

16. Krka Group

17. Valeant

18. Zydus Cadila

19. Par Pharmaceutical

20. Nichi-Iko Pharmaceutical

Taken remedial actions at two plants in Maharashtra: Drug firm Novartis

Drug firm Novartis today said it has taken remedial action at its two plants in Western India which

had received a warning letter from the US health regulator and expects the manufacturing facility to

returm to normal functioning soon.

Sandoz, the generic drug arm of Swiss drug major Novartis, had received a warning letter from the

US health regulator for violations of current good manufacturing practice (cGMP) norms at its two

plants in Maharashtra.

"Two Sandoz plants have received a warning letter from US Food and Drug Administration (USFDA).

We have already taken remedial action at these plants and these units would be soon back to

normal," Novartis India Managing Director and Vice Chairman, Ranjit Shahani told PTI on the

sidelines of an event here.

On October 22, 2015, the USFDA had issued a warning letter to the company's Sandoz Division

concerning Indian sites in Kalwe and Turbhe.

PHARMA UPTODAY

10

Both Turbhe and Kalwe fall in Maharashtra.

The warning letter observations followed USFDA inspection at both sites in August 2014 and are

related to deficiencies in current good manufacturing practice (cGMP) for finished pharmaceuticals.

At Turbhe, Sandoz mainly produces active pharmaceutical ingredients. In Kalwe oral solid dosages

or tablets are produced.

Novartis India shares today ended at Rs 848 a piece on the BSE, down 1.62 per cent from previous

close.

Well developed infrastructure and strong intellectual property rights in Switzerland provide an

incentive for companies to invest in innovation, Swiss Ambassador Linus von Castelmur said at an

event here.

Citing data from the European Patent Office (EPO), he said Switzerland filed 848 patents per one

million inhabitants, the most patents per capita, in 2014.

He was speaking at a conference here on 'Innovate or copy paste? A debate on innovation and

intellectual property in the health sector'.

"Switzerland's well developed infrastructure and strong intellectual property rights, which provide an

important incentive to invest in innovation by enabling firms to recover their investment costs,"

Castelmur said.

Hegemann said there should be predictable laws and regulations that reward innovations by way of

IPR protection.

Soumya Swaminathan, Director General of the Indian Council of Medical Research, emphasised the

importance of traditional medicine and traditional knowledge in the context of drug discovery.

"I think we still have a vast knowledge in the ancient systems of medicine both in Indian and Chinese

medicines...," she said, adding that it was an area being looked at.

Source: http://economictimes.indiatimes.com/

Pharma companies like Medtronic and Dr Reddy’s innovate with financing schemes for

cheaper treatment

Faced with mounting criticism over the high price of lifesaving drugs, pharma companies are

devising financing models that would let them have their cake and eat it too. The strategy allows the

companies to protect their key products from compulsory licensing and price controls, as well as

generate sales by making treatment more affordable for patients.

Companies such as Merck Sharp & Dohme (or MSD as US-based Merck & Co is known outside its

PHARMA UPTODAY

11

home market and Canada), Medtronic, Roche, Eisai and Dr Reddy's Laboratories are experimenting

with offers such as monthly installments, free diagnostic tests, discounts and even tailor-

made insurance schemes to make treatment affordable at a time when echoes of high drug prices

are reverberating from Asia to the Americas. MSD was one of the first to do this as the company

experimented with a monthly instalment scheme for its Hepatitis C injections, wherein it allowed

patients to pay in EMIfor the drug with an about 12 per cent interest rate.

Fullerton India, MSD's financing partner, said it lent to patients below its usual rates because the

drug maker subsidised the interest component. "We believe this market continues to remain

underserviced due to the complexities that exist," said Rakesh Makkar, executive vice president and

head of business and marketing at Fullerton India, adding that the company felt complexities should

not be a deterrent to grant credit.

Hyderabad-based Dr Reddy's has tied up with medical financing firm Arogya Finance to push its

brand of Hepatitis C drug Resof through a similar EMI scheme. The drug costs Rs 96,000 for a six-

month course and under the scheme, can be paid for over 24 months at an interest of 12 per cent.

Reddy's, according to people in the know, plans to extend this to its biosimilar cancer drug

Rituximab.

Lack of insurance is one of the key reasons that makes some patented drugs unaffordable in

countries like India. Most people in India spend on healthcare out of pocket, which becomes a

problem and push many into poverty when the cost of drug is high and the treatment is prolonged.

"Each year, nearly 30-40 million people fall into the poverty line because of unexpected health

shocks, and insurance schemes sometimes really do not address the immediate need," said Jose

Peter, one of the founders of Arogya Finance. The financial institution said it is targeting people with

an income of Rs 90,000 to Rs 2 lakh a year, who are neither covered under government insurance

schemes because they don't fall below the poverty line to avail of the benefit, nor can afford to make

bulk medical payments. In the case of the Hep C market, drug companies are also offering free

diagnostic tests to patients, in an attempt to create future customers for their drugs.

For more details browse:

http://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/pharma-

companies-like-medtronic-and-dr-reddys-innovate-with-financing-schemes-for-cheaper-

treatment/articleshow/49796186.cms

PHARMA UPTODAY

12

Three Dr Reddy’s sites hit with Warning Letters in India

Dr Reddy’s shares have slumped 14% after the company received an FDA Warning Letter

over manufacturing conditions at three Indian sites.

The US regulator found fault with API (active pharmaceutical ingredient) production facilities at

Srikakulam in the southeastern state of Andhra Pradesh and Miryalaguda in the southern state of

Telangana, as well as oncology formulation at Duvvada near Visakhapatnam, Andhra Pradesh.

The Warning Letter arrived after FDA inspections in November 2014, January 2015 and February

2015 respectively.

Dr Reddy’s CEO GV Prasad commented ―We take quality and compliance matters seriously and

standby our commitment to fully comply with the cGMP quality standards across all of our facilities.

―We will respond with a comprehensive plan to address these observations within the stipulated

time-frame of 15 days. We will continue to actively engage with the agency to resolve these issues

and we have also embarked on an initiative to revamp our quality systems and processes, as an

organization-wide priority.‖

Past problems

This time last year, the Skrikakulam API site was hit by an FDA Form 483 with nine observations

about the plant’s procedures, although a spokesperson at the time told in-Pharmatechnologist.com

―there is no implication on manufacturing and […] production continues as normal.‖

The Skrikakulam facility makes APIs for foreign export, including bromfenacna, celecoxib, ibuprofen,

ketorolac tromethamine, naproxen, naproxen sodium, glimeprid, linagliptin, liraglutide, and

nateglinide.

Pfizer gets OK for $160bn Allergan acquisition

The boards of Pfizer and Allergan yesterday signed a $160bn merger that will create the

world’s biggest pharmaceutical company.

The deal will allow chief executive Ian Read to register Pfizer in Ireland, a tax inversion that will cut

billions of dollars from the US company’s annual bill. The company plans to slash its tax rate from

around 25% to 17-18% within the year. Experts had speculated Pfizer might manage to bring the

rate below 7.5%, the lowest of any multinational.

Tax inversions have been criticised from many quarters, including Hillary Clinton, whose

spokesperson said she is ―committed to cracking down‖ on the accounting move which lets

companies ―leave the US on paper to game the tax system.‖

PHARMA UPTODAY

13

Although the US Treasury tightened rules on tax inversions last week, financial experts believe the

size of the companies involved in this deal, and Allergan’s high price tag, mean Pfizer will have no

barriers to the tax-swapping strategy it has openly pursued for several years.

Split to follow?

Pfizer said it expects the combined company to find $2bn in synergies over the next three years and

to reach cash flow of over $25bn from 2018. The mega-company will decide by 2018 whether to split

its innovative and established businesses.

The all-stock transaction, expected to close in the second half of 2016, is based on $363.63 per

Allergan share, and represents more than a 30% premium on the companies’ share prices at the end

of October.

Allergan brings with it several licenced and clinical-stage drug candidates, especially in women’s

health, anti-infectives, dermatology, eye care, gastrointestinal, neuroscience, and urology. The

companies’ combined mid-to-late stage programmes total more than 100 candidates.

Brent Saunders, who has been CEO of Allergan since Actavis bought the botox-maker earlier this

year and Allergan Chair Paul Bisaro will join Pfizer’s board.

Strides Shasun restarts API production at fire struck plant

Strides Shasun has restarted some active pharmaceutical ingredient (API) production at a

plant in Cuddalore, India after a fire last week.

The firm was ordered to halt product at the site by Indian authorities on November 16 according to a

document filed with the Bombay Stock Exchange .

Strides Shasun told today that ―We wish to inform you that the Cuddalore facility has been permitted

to resume operations in all manufacturing production blocks except the new production block [where

the fire took place.]”

The firm also said that the temporary suspension would not have a material impact on its revenues.

Strides Shasun was established this month by the merger of Strides Acrolab and Shasun

Pharmaceuticals.

The Cuddalore site – which was previously owned by Shasun – passed a World Health Organisation

(WHO) inspection in December 2012.

The focus of the visit was the production of the API Cycloserine , which is used in tuberculosis drugs

and is on the organisations essential medicines list .

The Cuddalore facility also produces APIs for ulcer medications – including Nizatidine and Ranitidine

– in addition to manufacturing excipients for various generic drugs.

PHARMA UPTODAY

14

Terminology

Audit trail:

An audit trail is a process that captures details such as additions,

deletions, or alterations of information in a record, either paper or

electronic, without obscuring or over-writing the original record. An audit

trail facilitates the reconstruction of the history of such events relating to

the record regardless of its media, including the ―who, what, when and

why‖ of the action. For example, in a paper record, an audit trail of a

change would be documented via a single-line cross-out that allows the

original entry to be legible and documents the initials of the person

making the change, the date of the change and the reason for the

change, as required to substantiate and justify the change. Whereas, in

electronic records, secure, computer-generated, time-stamped audit

trails at both the system and record level should allow for reconstruction

of the course of events relating to the creation, modification and deletion

of electronic data.

Computer-generated audit trails shall retain the original entry and

document the user ID, time/date stamp of the action, as well as a reason

for the action, as required to substantiate and justify the action.

Computer-generated audit trails may include discrete event logs, history

files, database queries or reports or other mechanisms that display

events related to the computerized system, specific electronic records or

specific data contained within the record.

Ref: GUIDANCE ON GOOD DATA AND RECORD MANAGEMENT PRACTICES - WHO

PHARMA UPTODAY

15

New Guidance Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment

Guidance for Industry

This guidance provides recommendations for the development of antiretroviral drugs regulated within

the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) for the

treatment of human immunodeficiency virus-1 (HIV-1 or HIV) infection. Specifically, this guidance

addresses the FDA’s current thinking regarding the overall development program and clinical trial

designs for antiretroviral drugs to support an indication for the treatment of HIV-1 infection. The

organization of the guidance parallels the development plan for a particular drug or biologic.

This guidance does not address the use of antiretroviral drugs for preventing transmission of HIV-1

infection. Also, this guidance does not address the development of therapeutics without antiviral

mechanisms, intended to mitigate or reverse clinical or pathophysiological outcomes of immunologic

suppression caused by HIV-1 infection.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance

s/UCM355128.pdf

Manual of Policies and Procedures: MAPP 5018.2 NDA Classification Codes

The NDA classification code provides a way of categorizing new drug applications. The code

evolved from both a management and a regulatory need to identify and group product applications

based on certain characteristics, including their relationships to products already approved or

marketed in the United States. Classifying applications based on these characteristics contributes to

the management of CDER’s workload, promotes consistency across review divisions, enables

retrospective analysis of trends, and facilitates planning and policy development.

Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobac

co/CDER/ManualofPoliciesProcedures/UCM470773.pdf

Investigational New Drug Applications (INDs) — Determining Whether Human Research

Studies Can Be Conducted Without an IND Guidance for Industry

This guidance is intended to assist clinical investigators, sponsors, sponsor-investigators and

institutional review boards (IRBs) in determining whether research studies involving human subjects

must be conducted under an investigational new drug application (IND), as described in title 21 of

the Code of Federal Regulations, part 312 (21 CFR part 312) (the IND regulations). This guidance

describes when an IND is required, specific situations in which an IND is not required, and a range of

issues that, in FDA’s experience, have been the source of confusion or misperceptions about the

application of the IND regulations. This guidance addresses only whether an IND is needed. If your

PHARMA UPTODAY

16

study also involves the use of a device, you should determine whether such use is subject to 21 CFR

part 812 (the IDE regulations).

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance

s/UCM229175.pdf

New WHO Draft on "Good Data and Record Management"

WHO has released the draft of a guideline - after a one-year development phase - "Good Data and

Record Management Practices" which can be commented on until 30 November 2015.

A substantial part of the decisions taken by the authorities with regard to the regulated industry are

based on dossiers. For this reason, their data have to meet the ALCOA principles (Accurate / Legible

/ Contemporaneous / Original / Attributable). Although those principles aren't new, an increasing

number of observations with regard to "Good Data Management" in the area of GMP, GCP and GLP

have been made during inspections in the last years. The reasons for this are manifold.

The present WHO draft on "Good Data Management" should bring together all the existing normative

principles and close the gaps left behind in the current guidelines. The focus is on those principles

which are already listed in existing WHO guidelines and which have an influence on data integrity

and reliability.

The draft itself is sectioned as follows:

Introduction and background

Aims and objectives of this Guidance

Glossary

Principles

Quality risk management to ensure Good Data Management

Management governance and quality audits

Contracted organizations, suppliers, and service providers

Training in Good Data and Record Management

Good Documentation Practice

Designing Systems to assure data quality and reliability

Managing data and records across the data lifecycle

Addressing data reliability issues

References and further reading

Refer: http://www.who.int/medicines/areas/quality_safety/quality_assurance/Guidance-on-good-data-

management-practices_QAS15-624_16092015.pdf

PHARMA UPTODAY

17

USP revises Chapter <1231> on Pharmaceutical Water

Changes to the fundamental monograph on pharmaceutical water <1231> Water for Pharmaceutical

Purposes from the US-American Pharmacopeia have been published for comments in the

Pharmacopeial Forum 41(5). The revision presented in the current draft mainly has a structural

nature. The content of the monograph has been reorganised in 9 new chapters which aim at

improving readibility and searchability of the content searched:

1. INTRODUCTION

2. SOURCE WATER CONSIDERATIONS

3. WATERS USED FOR PHARMACEUTICAL MANUFACTURING AND TESTING PURPOSES

4. VALIDATION AND QUALIFICATION OF WATER PURIFICATION, STORAGE, AND

DISTRIBUTION SYSTEMS

5. DESIGN AND OPERATION OF PURIFIED WATER AND WATER FOR INJECTION SYSTEMS

6. SAMPLING

7. CHEMICAL EVALUATIONS

8. MICROBIAL EVALUATIONS

9. ALERT AND ACTION LEVELS AND SPECIFICATIONS

The deadline for comments is 20 November 2015.

Draft of new Ph. Eur. Chapter "Co-Processed Excipients" published

A draft of a new Ph. Eur. chapter "Co-Processed Excipients" has been published in Pharmeuropa

27.4 with deadline for comments on December 31, 2015.

In the proposed chapter a co-processed excipient is defined as "any combination of two or more

excipients obtained by physical co-processing that does not lead to the formation of covalent bonds".

The individual components of a co-processed excipient have to comply with the requirements of any

corresponding individual Ph. Eur monograph and of the general Ph. Eur. monograph Substances for

pharmaceutical use. Additionally, the co-processed excipients comply with the requirements of the

general Ph. Eur. monograph Substances for pharmaceutical use.

Co-processed excipients can be produced by processings that produce only a physical interaction

between the components like for example co-drying, spray drying, granulation, extrusion, and high-

shear dispersion. They may be batch or continuous processes.

The proposed monograph includes sections on Characters, Identification, Tests, Assay,

Labelling, and Functionality-Related Characteristics.

PHARMA UPTODAY

18

The section on "Tests" proposes that "specifications are defined for the final co-processed material

as a whole" and "if the co-processed excipient includes impurities not controlled by the monographs

of the individual components, these must be specified and suitably controlled".

New USP General Chapters on Extractables and Leachables: <1663>, <1664>

Two new USP General Chapters on extractables and leachables which had been proposed in

Pharmacopeial Form 39 (5) have become official on August 1, 2015 (USP 38-NF33, first

supplement):

<1663> Assessment of Extractables Associated with Pharmaceutical

Packaging/Delivery Systems and

<1664> Assessment of Drug Product Leachables Associated with Pharmaceutical

Packaging/Delivery systems.

These chapters are intended to be informational. They provide a framework for the design,

justification, and execution of extractables/leachables assessments for pharmaceutical packaging

systems. They do not present specific experimental conditions, specific tests, analytical procedures

or acceptance limits for packaging systems or products.

Additionally, the PSD Expert Committee plans a general chapter <1665> on the Toxicological Safety

Assessment of Extractables and Leachables (announced in PF and 39(6)). The chapter is expected

to provide a framework for performing a toxicological safety assessment. It is not expected to provide

specific protocols or specifications.

However, the above mentioned General Chapters might get a more official character when

implemented in USP Monographs or General Chapters on dosage forms products-quality tests. In

the recent issue of PF 41(5) reference to the two new Chapters <1663> and <1664> has been

integrated in the Drafts of General Chapters on Ophthalmic Products <771> and Injections <1>.

Therefore, in future, it might be necessary to discuss the scientific principles and best demonstrated

practices for extractables/leachables studies. In addition, the assessment of possible

leachables/extractables and the establishment of acceptance criteria for these substances might be

based on risk assessments for a specific combination of product, indication, route of administration,

and packaging system. The comment deadline for the in PF 41(5) proposed chapters is November

30, 2015.

FDA extends comments for "established conditions" guidance

PHARMA UPTODAY

19

In the October 6, 2015, Federal Register, the FDA announced that they are reopening the comment

period for the "Established Conditions: Reportable Chemistry, Manufacturing, and Controls ("CMC")

Changes for Approved Drug and Biologic Products; Draft Guidance for Industry." Comments are now

due January 4, 2016. The FDA is reopening the comment period for additional 90 days to allow

interested persons more time to submit comments on these important issues.

The FDA guidance documents, such as "CMC Post-approval Manufacturing Changes To Be

Documented in Annual Reports" intend to clarify the recommended reporting mechanism (i.e.,

supplement, annual report) for post-approval CMC changes.

The present draft guidance document identifies "those sections of a CTD-formatted application that

typically contain information that FDA considers to meet the definition of established conditions".

It is expected that a better understanding of "established conditions" will allow for more effective

post-approval change management strategies e.g. by the use of risk management principles (ICH

Q9), and knowledge management (ICH Q10). Additionally, this will also provide more regulatory

flexibility. In future, an applicant could probably rely upon a robust Pharmaceutical Quality System

(PQS) to handle post -approval changes appropriately, resulting in a reduction (or elemination) of

certain reporting requirements.

What are "established conditions" for manufacturing and control?

This is a highly discussed topic in context of the planned new ICH Q12 Guideline "Lifecycle

Management". The FDA defines established conditions as "the description of the product,

manufacturing process, facilities and equipment, and elements of the associated control strategy, as

defined in an application, that assure process performance and quality of an approved product.

Changes to the established conditions must be reported to the FDA".

An example given in the draft guidance document is:

"if on-line, real-time attribute monitoring is implemented post-approval for a particular unit operation,

it may be acceptable to designate the on-line monitoring (e.g., NIR analysis) as an established

condition, while removing the inputs and process parameters for the unit operation from the

established conditions".

Source: http://www.gpo.gov/fdsys/pkg/FR-2015-10-06/pdf/2015-25356.pdf

http://www.gmp-compliance.org/guidemgr/files/UCM448638.PDF

PHARMA UPTODAY

20

Recently posted US FDA guidance documents:

11/6/15: Guidance for Industry: Questions and Answers on FDA’s Fortification Policy

11/16/15: Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products

for Over-the-Counter Human Use

11/17/15: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or

Applicants

11/17/15: Class II Special Controls Guideline: In Vitro Diagnostic Devices for Bacillus spp. Detection

- Draft Guideline for Industry and Food and Drug Administration Staff

11/19/15: Draft Guidance for Industry: Voluntary Labeling Indicating Whether Food Has or Has Not

Been Derived From Genetically Engineered Atlantic Salmon

11/20/15: Nonprescription Sunscreen Drug Products - Content and Format of Data Submissions to

Support a GRASE Determination Under the Sunscreen Innovation Act

11/20/15: Over-the-Counter Sunscreens: Safety and Effectiveness Data Guidance for Industry

11/20/15: Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process

11/20/15: Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request Guidance

for Industry

PHARMA UPTODAY

21

AUDIT FINDINGS - 483 Observations

Firm Name 483 Observation

UPM Pharmaceuticals - Aug.

14, 2015

Complaint records are deficient in that they do not include the

findings of the investigation and follow-up.

Diabetes Corp. of America -

Aug. 20, 2015

Drug product containers and closures were not sterilized and

processed to remove pyrogenic properties to assure that they are

suitable for their intended use.

Uriel Pharmacy, Inc. - Sept. 3,

2015

There are no written procedures for production and process

controls designed to assure that the drug products have the

identity, strength, quality, and purity they purport or are

represented to possess.

Sperian Eye & Face

Protection, Inc. - Sept. 21,

2015

Procedures designed to prevent objectionable microorganisms in

drug products not required to be sterile are not established.

Estee Lauder, Inc. (Len Ron

Mfg.) - Aug. 6, 2015

The quality control unit lacks the responsibility and authority to

reject all drug products.

Cosmetic Specialty Labs, Inc. -

Sept. 11, 2015

Written procedures are not drafted, reviewed and approved by the

appropriate organizational units and reviewed and approved by

the quality control unit.

Mountain Spirit LLC dba Mountain Spirit Herbal Co. - Sept. 30, 2015

There is no quality control unit.

Gulbrandsen Technologies - Aug. 26, 2015

The firm failed to perform process validation for an active

pharmaceutical ingredient (API) manufacturing process.

GenPak Solutions, LLC - Aug. 12, 2015

The responsibilities and procedures applicable to the quality

control unit are not fully followed.

Smith & Vandiver Corp. - Aug. 26, 2015

Drug products do not bear an expiration date determined by

appropriate stability data to assure they meet applicable standards

of identity, strength, quality and purity at the time of use.

Coastal Meds, LLC - Sept. 23, 2015

Aseptic processing areas are deficient regarding the systems for

monitoring environmental conditions.

Qualgen, LLC - Sept. 17, 2015 The separate or defined areas and control systems necessary to

prevent contamination or mix-ups are deficient.

Allergan Sales, LLC - Oct. 8, 2015

The written stability program for drug products does not include

sample size and test intervals based on statistical criteria for each

attribute examined to assure valid estimates of stability.

BASF Corp. - Oct. 23, 2015 Written procedures are not followed for the completion of the

PHARMA UPTODAY

22

Product Review and the closing out of change control documents.

Creative Fragrances, Ltd. - Oct. 13, 2015

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the identity and strength of each active ingredient prior to release.

Downing Labs, LLC - Oct. 9, 2015

There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

Goodier Cosmetics, LP - Oct. 8, 2015

Component testing is deficient in that each component is not tested for conformity with all appropriate written specifications for purity, strength, and quality.

Akorn, Inc. - June 5, 2015 Deviations from written specifications, standards, and test procedures are not justified.

US FDA publishes 483 issued to Diabetes Corporation of America (Producer of Sterile Drug

Products):

Observations:

1. Drug product containers and closures were not sterilized and processed to remove pyrogenic

properties to assure that they are suitable for their intended use.

2. Aseptic processing areas are deficient regarding the system for monitoring environmental

conditions.

3. Aseptic processing areas are deficient regarding systems for maintaining any equipment used

to control the aseptic conditions

4. Each batch of drug product purporting to be sterile and pyrogen-free is not laboratory tested

to determine conformance to such requirements.

5. Procedures designed to prevent microbiological contamination of drug products purporting to

be sterile are not established.

6. Clothing of personnel engaged in the processing of drug products is not appropriate for the

duties they perform.

7. There is no written testing program designed to assess the stability characteristics of drug

products.

8. Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the

room to produce aseptic conditions.

9. Time limits are not established when appropriate for the completion of each production phase

to assure the quality of the drug product

PHARMA UPTODAY

23

US FDA publishes 483 of Pine Pharmaceuticals (Outsourcing facility):

Observations:

1. There is a failure to thoroughly review the failure of a batch or any of its components

to meet any of its specifications whether or not the batch has been already

distributed.

2. Aseptic processing areas are deficient regarding systems for maintaining any

equipment used to control the aseptic conditions.

3. For each batch of drug product, there shall be appropriate laboratory determination

satisfactory conformance to final specifications for the including identity and strength

active ingredient, prior release.

4. The labels and containers of your outsourcing facility's drug products do not include

information required by section 503B(a)(10)(A) (B).

5. Your outsourcing facility has not submitted a report to FDA identifying all products

compounded during the previous six month period as required by section

503B(b)(2)(A).

FDA Warning letters

US FDA Warning letter: American Family Pharmacy (pharmaceutical manufacturing facility)

Current Good Manufacturing Practice Violations

1. Your firm failed to follow written procedures applicable to the quality control unit (21 CFR

211.22(d)).

You gave all these lots, produced over five months, a single lot number: ―12084.‖ This

negated your ability to differentiate between lots.

your firm distributed these ―12084‖ lots with no review from your firm’s quality unit to

ensure the identity, strength, quality, and purity of your drug products. This

contradicts your ―Responsibilities of the Quality and Production Units‖ SOP.

Your quality unit did not review these lots prior to release for distribution.

PHARMA UPTODAY

24

2. Your firm does not have, for each batch of drug product, appropriate laboratory determination of

satisfactory conformance to final specifications for the drug product, including the identity and

strength of each active ingredient prior to release (21 CFR 211.165(a)).

you distributed multiple lots of 81 mg aspirin tablets without finished product testing

your product failed to meet the USP specifications for assay, content uniformity, and

dissolution.

tablet color was inconsistent.

You did not investigate customer complaints about inconsistently colored tablets.

3. Your firm failed to establish and follow procedures for the receipt, identification, storage,

handling, sampling, testing, and approval or rejection of components and drug product containers

and closures (21 CFR 211.80(a)).

you did not establish specifications and procedures to evaluate whether active blends

4. Your firm failed to establish adequate written procedures for production and process control

designed to assure that the drug products you manufacture have the identity, strength, quality, and

purity they purport or are represented to possess (21 CFR 211.100(a)).

your firm does not have evidence that your processes

unable to provide any validation documentation

Your firm also lacked sufficient batch instructions to ensure reproducibility

Your firm’s batch records do not include complete documentation

5. Your firm failed to assure that drug products bear an expiration date determined by appropriate

stability testing. (21 CFR 211.137).

You did not monitor or evaluate the stability of these products. Their expiration dates

are not based on any supportive initial or ongoing stability studies.

6. Your firm failed to establish and follow written procedures designed to assure that correct labels,

labeling and packaging are used for drug products (21 CFR 211.130).

you did not follow your firm’s SOP, ―Lot Number Creation.‖

Misbranding Violations

PHARMA UPTODAY

25

The immediate container label does not include the Reye’s Syndrome Warning and Stomach

Bleeding Warning, as required under 21 CFR § 201.314 and 21 CFR § 201.326.

The Stomach Bleeding Warning on the outer container is also incomplete. It fails to include

the word ―severe‖ within the first line of the warning.

The ―take a blood thinning (anticoagulant) or steroid drug‖ bullet is missing. Therefore, the

product is misbranded under sections 502(f)(2) and 502(a) of the Act [21 U.S.C. 352(f)(2) and

352(a)].

It failed to meet the USP dissolution specifications for delayed released tablets in accordance

with 21 CFR §343.90 (c), which states, ―aspirin delayed-release tablets must meet the

dissolution standard for … aspirin delayed-release tablets as contained in U.S.P, XXI

Supplement 3 at page … 1973.‖

US FDA Warning letter - Dr. Reddy's Laboratories Limited (WL: 320-16-02):

The U.S. Food and Drug Administration (FDA) inspected the following three Dr. Reddy’s

Laboratories Ltd. pharmaceutical manufacturing facilities in India:

A. November 17-21, 2014: Dr. Reddy’s Laboratories Limited CTO Unit VI, located at APIIC

Industrial Estate, Pydibhimavarma (Village), Ranasthalam Mandai, Srikakulam District,

Andhra Pradesh (FEI: 3002949085)

1. Failure to maintain complete data derived from all laboratory tests conducted to ensure

compliance with established specifications and standards.

Your laboratory records did not contain all raw data generated during each test for API

batches manufactured at your firm

failing or atypical results were not investigated or included in the official laboratory

control records.

presence of an uncontrolled ―Custom QC laboratory‖ (CQC) was discovered by our

inspection team. The existence of this laboratory was previously unknown to FDA

failing result was not documented or reported; repeated the analysis, with a failing

result again, did not documented or reported. Laboratory’s ―Record of Analysis‖ for this

batch, which you used to support batch disposition decisions, contained only the

passing results obtained during the third and final test

PHARMA UPTODAY

26

This sample failed the purity specification limit, but you did not document, report or

investigate the failure.

The first sample analysis for related substances by HPLC was performed in duplicate

at (b)(4) February 10, 2012. The second injection of this first sample contained an extra

peak. Sample preparation information was not documented, and the test result with the

extra peak was not reported.

Only the third failure was reported in your QC data package, which you used to support

batch disposition decisions. Sample preparation information for the first two sequence

runs was not documented.

2. Failure to prevent unauthorized access or changes to data, and to provide adequate controls to

prevent omission of data.

Uncontrolled access to electronic systems used to generate data in your Product

Development Laboratory (PD Lab).

HPLC systems are configured so that no passwords are required to log in

there is no electronic or procedural control to prevent manipulation of data

HPLC system had no access controls to prevent alteration or deletion of data

HPLC software lacked an audit trail feature to document all activities related to the

chromatographic analysis.

unknown individual had logged into the system using the analyst’s credentials. This

unknown individual performed injections and deletions without the analyst’s knowledge.

3. Failure to record activities at the time they are performed.

employees did not complete batch production and control records immediately after

activities were performed.

eight production records had blank entries for weights of material used for production,

checked-by signatures, accessories used, in-house batch numbers, quantity added,

and product labeling for material dried specimens. The yield report sheet and batch

summary sheet were also incomplete.

Missing information was recorded on uncontrolled sheets of paper instead of in your

official records.

4. Failure to control the issuance, revision, superseding and withdrawal of all documents with

maintenance of revision histories

PHARMA UPTODAY

27

o copies of issued, partially-used and unused batch records, analytical raw data,

analytical results, training records, and cleaning validation protocols in the waste area.

These controlled documents had not been completed or archived in accordance with

your SOP on documentation practices.

master batch records in the manufacturing areas, even though they were required to

remain under the control of the quality unit. We also found a production employee with a

quality unit document control stamp.

B. January 26-31, 2015: Dr. Reddy’s Laboratories Limited CTO Unit V, located at

Peddadevulapally Village, Tripuraram, Mandal, Miryalguda Taluk, Nalgonda District,

Telangana;(FEI: 3005447965)

1. Failure to adequately investigate out-of-specification results and implement appropriate

corrective actions.

o 11 batches had failed the optical purity test, and that you had been unable to determine

a root cause for such failures.

o 65 batches of this intermediate failed to meet the single impurity

specification. The failure rate you acknowledged as high.

2. Failure to maintain all quality-related documents appropriately.

o ―Documentation Control, Archival and Destruction,‖ does not permit photocopying

labels, during the inspection we observed numerous pre-filled, photocopied labels in

the garbage. These photocopied labels included the name of the product, material

code, batch number, drum number, net weight, batch quantity, signature and date.

3. Failure to prevent unauthorized access or changes to data.

o QC laboratory analysts were authorized to release finished product in your firm’s

computerized SAP inventory management system. Release or rejection of finished

product is a non-delegable responsibility of the quality unit, and cannot be shared with

laboratory analysts or other personnel. However, your SAP system permitted QC

laboratory analysts to release intermediates from one process to the next process, as

well as to release finished product into the market without requiring quality unit

oversight.

4. Failure to identify storage containers for intermediates in batch production records.

PHARMA UPTODAY

28

o you had not recorded identification numbers in your product batch records for drums

used to hold intermediates during manufacturing. We also observed that you had not

implemented necessary controls to prevent mix-ups and contamination.

o

C. February 26 to March 6, 2015: Dr. Reddy’s Laboratories Ltd., Unit-VII located at Plot No.

P1 to P9, Phase III, Duvvada, VSEZ, Visakhapatnam, Andhra Pradesh. (FEI: 3006549835)

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or

any of its components to meet any of its specifications, whether or not the batch has already been

distributed. (21 CFR 211.192)

o filling operation, our investigator documented a malfunction in the mechanism used to

transport filled vials. The mechanism approximately correct before it malfunctioned and

stopped. your management failed to intervene, and allowed the filling process to

continue uninterrupted. operator repeatedly using forceps and hand to manually and

align with the conveyor belt.

o Each of these manual interventions risks compromising the sterility of the product and

is a deviation from your approved SOP.

o You did not simulate these critical manual interventions during media fills, so you have

no basis to know whether they may compromise the sterility of your products.

2. Your firm failed to follow appropriate written procedures designed to prevent microbiological

contamination of drug products purporting to be sterile, and that include validation of all aseptic and

sterilization processes (21 CFR 211.113(b)).

o Your media fill record reconciliation documentation failed to include a full accounting

and description of the units rejected from each batch.

3. Your firm failed to establish adequate written procedures for production and process controls

designed to assure that the drug products you manufacture have the identity, strength, quality, and

purity they purport or are represented to possess, and your firm’s quality control unit did not review

and approve those procedures, including any changes. (21 CFR 211.100(a))

o you did not document the creation of inspectors’ qualification kits.

o The challenge test set vials used to qualify your operators were inadequate because

particle size in the kits is not specified.

PHARMA UPTODAY

29

US FDA Warning letter - Sandoz Private Limited (WL: 320-16-01):

The U.S. Food and Drug Administration (FDA) inspected the following two pharmaceutical

manufacturing facilities:

A. August 25-29, 2014: Sandoz Private Limited, MIDC Plot Nos. 8-A/2 & 8-B, TTC Industrial

Area, Kalwe Block, Village Dinghe, Navi Mumbai 400 708, Maharashtra, India (Kalwe

facility) (Finished Dosage Manufacturing Site FEI #3004944629)

1. Your firm failed to prepare batch production and control records for each batch of drug product

that include documentation of the accomplishment of each significant step in the manufacture,

processing, packing, or holding of the batch (21 CFR 211.188(b)).

o non-contemporaneous documentation of batch production activities. Two uncontrolled

Excel spreadsheets were used to record discrepancies and certain in-process drug

quality data. This data was initially missing in the batch manufacturing record. Your firm

later entered this data into batch records and backdated them.

o entry in one spreadsheet, you did not perform testing as required after operations

of batch

2. Your firm failed to maintain adequate written records of major equipment maintenance (21 CFR

211.182).

o original preventive maintenance work orders in trash bags.

o A partially-completed document retrieved from the waste receptacle included

handwritten notes about the condition of equipment observed during preventive

maintenance.

3. Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or

holding of a drug product has the education, training, and experience, or any combination thereof, to

enable that person to perform his or her assigned functions, and that training in current good

manufacturing practice is conducted by qualified individuals (21 CFR 211.25(a)).

o your contract employee who trains other contract employees on good documentation

practices was unable to explain the material he was required to present during training.

o a significant number of your contract employees do not speak English, you only

provided English training materials to these employees.

o employee’s failing equipment qualification training assessment form in the trash, yet

that employee’s official file showed passing results.

PHARMA UPTODAY

30

4. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch, or

any of its components, to meet any of its specifications, whether or not the batch was already

distributed (21 CFR 211.192).

failed to investigate an out-of-specification impurity result for the stability interval

of exhibit batch

Although this exhibit lot was not distributed, you did not evaluate the impact of this

failure mode on the quality of other lots of product.

5. Your firm failed to exercise appropriate controls over computer or related systems to assure that

only authorized personnel institute changes in master production and control records, or other

records (21 CFR 211.68(b)).

o no access restrictions to laboratory data generated by the instrument used to test and

release raw materials and in-process drug products.

o Your laboratory computer systems lack necessary controls to prevent data tampering

and to detect data that may have been compromised.

B. August 12-28, 2014: Sandoz Private Limited, Plot Nos. D31 & D32, MIDC, TTC Industrial

Area, Turbhe, Thane-Belapur Road, Navi Mumbai 400 705 Maharashtra, India (Turbhe

facility) (Active Pharmaceutical Ingredient and Finished Dosage Manufacturing Site FEI

#3003737804)

1. Your firm failed to establish and follow appropriate written procedures that are designed to

prevent microbiological contamination of drug products purporting to be sterile, and that include

validation of all aseptic and sterilization processes (21 CFR § 211.113(b)).

failed to perform adequate unidirectional airflow studies (smoke studies) on the aseptic

filling line used to produce sterile finished drug products.

failed to establish procedures to remove units following interventions, periodic

adjustments, set-up, and end of fill. Furthermore, your firm rejected units with intact

container/closure systems from media fills without written justification or explanation.

2. Your firm failed to establish an adequate system for monitoring environmental conditions in

aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

inadequate scientific justification for your environmental monitoring sampling plans in

manufacturing areas for aseptically-filled injectable drug products.

PHARMA UPTODAY

31

For improvement ….

• Accurately record actions taken during

method validation.

The project status may change and if the work

needs to be resumed at a later date, time

won’t be lost repeating work that was already

completed.

PHARMA UPTODAY

32

Article of the Month

Data Integrity Checklist related to Electronic Records and Electronic Signatures Electronic Record System Controls

Validate system Generate records Protect records Limit access Use audit trails Enforce workflow Check authority Check input Train users Establish policies Control system documentation

Electronic Signature Printed name of signer Date/time of signing Meaning of signature Electronic record system controls Linked to electronic record such as to prevent falsifying

Electronic Signature Requirements Unique to owner Owner has proven his/her identity Acknowledgement as legally binding

Electronic Signature Components & Controls Based upon two identification components Both components used at first signing One component used in subsequent serial signings Used only by owner Falsification requires collusion

Controls for Identification Components Uniqueness Periodic maintenance Use loss management Transaction safeguards Periodic testing of identification devices

PHARMA UPTODAY

33

Regulations of the Month

Subpart C--Buildings and Facilities

Sec. 211.46 Ventilation, air filtration, air heating and cooling.

(a) Adequate ventilation shall be provided.

(b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and

temperature shall be provided when appropriate for the manufacture, processing, packing, or

holding of a drug product.

(c) Air filtration systems, including prefilters and particulate matter air filters, shall be used

when appropriate on air supplies to production areas. If air is recirculated to production areas,

measures shall be taken to control recirculation of dust from production. In areas where air

contamination occurs during production, there shall be adequate exhaust systems or other

systems adequate to control contaminants.

(d) Air-handling systems for the manufacture, processing, and packing of penicillin shall be

completely separate from those for other drug products for human use.

Sec. 211.48 Plumbing.

(a) Potable water shall be supplied under continuous positive pressure in a plumbing system

free of defects that could contribute contamination to any drug product. Potable water shall

meet the standards prescribed in the Environmental Protection Agency's Primary Drinking

Water Regulations set forth in 40 CFR part 141. Water not meeting such standards shall not

be permitted in the potable water system.

PHARMA UPTODAY

34

Top Presentations of Pharma Uptoday

· Presentation on data integrity in Pharmaceutical Industry

· Data Integrity II - Chromatography data system (CDS) in Pharma

· Good chromatographic practices

· HPLC - Peak integration for chromatography

· Good Laboratory Practices for Pharmaceutical Quality Control Laboratories

· Laboratory Errors

· Understand the importance of each step to minimise Laboratory errors

· Sample preparation techniques of solid dosage forms

· Investigating aberrant potency values in Pharma Analysis

· All about Tablets (Pharma)

The module Consult Yourself.... “Know Regulation - No Observation” deals with most common

(top 20) basic CFR regulations having frequent violations and previous observations for better

understanding.

#1 "21 CFR 211.160" http://www.slideshare.net/skvemula/top-20-observation-series-1-21-cfr-211160

(Subpart I--Laboratory Controls: Sec. 211.160 General requirements.)

#2 "21 CFR 211.22" http://www.slideshare.net/skvemula/top-20-observation-series-2-21-cfr-21122

(Subpart B--Organization and Personnel: Sec. 211.22 Responsibilities of quality control unit)

#3 "21 CFR 211.192" http://www.slideshare.net/skvemula/top-20-observation-series-3-21-cfr-211192

(Subpart J--Records and Reports: Sec. 211.192 Production record review.)

#4 "21 CFR 211.67" http://www.slideshare.net/skvemula/top-20-observation-series-4-21-cfr-21167

(Subpart D—Equipment: Sec. 211.67 Equipment cleaning and maintenance)

#5 "21 CFR 211.100" http://www.slideshare.net/skvemula/top-20-observation-series-5-21-cfr-211100

(Subpart F- Production and Process Controls: Sec. 211.100 Written procedures; deviations.)

PHARMA UPTODAY

35

#6 "21 CFR 211.165" http://www.slideshare.net/skvemula/top-20-observation-series-6-21-cfr-211165

(Subpart I--Laboratory Controls: Sec. 211.165 Testing and release for distribution)

#7 "21 CFR 211.42" http://www.slideshare.net/skvemula/top-20-observation-series-7-21-cfr-21142-

subpart-cbuildings-and-facilities-design-and-construction-features

(Subpart C-Buildings and Facilities – Design and construction features)

Few Pharma Uptoday topics can be accessed from our website

https://sites.google.com/site/pharmauptoday/

Few Pharma Uptoday presentations can be accessed from our website

http://www.slideshare.net/skvemula

To subscribe free online daily Newsletter write a mail to

pharmauptoday@gmail.com with subject “Add mail”.