What are “complex manufacturing processes”? A recent reply from the EMA




Sometimes a clear definition of terms is crucial in the communication between authorities and pharmaceutical companies. Find out what the European Medicines Agency EMA defines as “complex manufacturing steps” and what authorisation holders providing a variation application need to consider.



The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure for variations of existing marketing authorisations. The “detailed guidelines for the various categories of variations“, which were published in the consolidated version in August 2013 in the European Official Journal, explain the interpretation and application of this Variations Regulation.

Although the “detailed guidelines” describe a number of scenarios of possible variations in some detail, there are formulations in the Guideline text which require clarification due to their blur. The EMA adopted such a case in a recent update of itsquestions and answers collection “Quality of Medicines Questions and Answers: Part 1” to concretise the case through a statement.

It is about the term “complex manufacturing processes”, which is used in two scenarios associated with type II variations (found in the “detailed guidelines” p 40ff):

  • Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product (Guideline change code B.II.b.1)

    c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes.
  • Change in the batch size (including batch size ranges) of the finished product (Guideline change code B.II.b.4)

    d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes .

The EMA now clarified this term as follows:

  • Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the understanding of the relation between quality characteristics of the product and its in vivo efficacy is lacking. This is often the case in innovative medicines such as products of nanomedicine.
  • Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain one or more sub-steps, where a scale-up can lead to problems.

In both scenarios, the approving authority will decide on a case by case basis. If the applicant submits the variation as a Type IB, he must provide a valid justification that the production process is not “complex”. However, in doubt the authority may upgrade the variation to a Type II. Therefore, the EMA recommends that the applicant clarifies the situation with the authority before submitting the variation


Japan’s drug regulator PMDA set to open office in India

HYDERABAD: Japan’s drug regulator, the Pharmaceuticals and Medical Devices Agency (PMDA), is set to open an India office soon, amid concerns over an aging population and burgeoning healthcare costs in a country dominated by branded drugs.

The move is expected to help Indian generic drug manufacturers, which have been seeking to increase their presence in Japan either through exports or by forging joint ventures with partners in that country. Japan’s market, the second-largest in the world after the US, is worth $110 billion.





/////////Japan,  drug regulator, PMDA ,  open office, India

Unimark Remedies Ltd, WARNING LETTER

Warning Letter
VIA UPS                                                                                           
WL: 320-15-17
September 28, 2015
During our March 18-21, 2014 inspection of your pharmaceutical manufacturing facility, Unimark Remedies Ltd., located at 337 Kerala Nalsarovar Road, Kerala Village, Bavla, Ahmedabad District, India, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).
These deviations cause your APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B). The methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
Mehul Parekh
Entrepreneurs: Healthy outlook
Though careers in this field are cropping up, it’s tough for entrepreneurs to find a foothold. “When I started my business, I took whatever work came my way. Beggars can’t be choosers and neither can start-ups,” says Mehul Parekh, MD and founder, Unimark Remedies. Parekh always knew he wanted to be an entrepreneur but couldn’t make up his mind about the field. He studied to become a chartered accountant and worked for six months to learn the ropes of running a business.In 1982, Parekh set up Rainbow Fine Chemicals, a pharmaceutical marketing company with Rs 3 lakh as seed money. However, Parekh knew that the opportunity and money were in making medicines. So, after his brother got a master’s degree in organic chemistry, Parekh decided to venture into the field confident in the knowledge that he could bank on his brother’s expertise. In 1995, he set up a manufacturing unit and renamed his company Unimark Remedies. “The biggest challenge is always funding. I bought the premises simply because the owner was the only one willing to sell it on credit,” says Parekh. In 1997, he purchased another plant, this time promising the owner that if he put in the capital, he would get to share the profits. “I avoid putting in huge amounts because it blocks the money that can be invested in more important areas,” he adds.

Besides funding, another roadblock faced by entrepreneurs is government regulations. Concurs Das: “Some subjects, such as highway emergency, are nobody’s baby. The police dumps it on the Transport Department, which says it’s a Health Ministry issue, which, in turn, states accidents to be a police matter.” If such issues were to deter people like Das, the healthcare sector would be in a comatose state. The fact that it has begun to emerge from it speaks volumes about the healthy outlook of such entrepreneurs.

Kerala Nalsarovar Road, Kerala Village, Bavla, Ahmedabad District, India,


The new APIC Guidance on Handling of Insoluble Matter and Foreign Particles in the Manufacture of Active Pharmaceutical Ingredients

The new APIC Guidance on Handling of Insoluble Matter and Foreign Particles in the Manufacture of Active Pharmaceutical Ingredients

The occurrence of foreign particles in the manufacture of active pharmaceutical ingredients is always undesirable. For the responsible QA departments it involves an increased effort as concerns the search for the root causes and for CAPA measures. A new APIC Guidance offers concrete recommendations for the GMP compliant handling of foreign particles in APIs, intermediates and raw materials.

Foreign particles in APIs or medicinal preparations are undesirable and sometimes lead to a recall of the batches concerned. Depending on the type of particles their presence in active pharmaceutical ingredients may be harmless; in many cases they are inevitable. In any case the manufacturer must find an adequate way how to handle those impurities visible to the human eye. The search for a guideline or another official document in the relevant regulations is in vain. Visible particles or fibres are only mentioned in the USP chapter <790>, in chapter 2.9.20 of the European Pharmacopoeia as well as in the United States Food, Drug and Cosmetic Act (FD&C Act).

In order to remedy this lack of guidance or recommendations a group of experts within APIC has drawn up a guidance on the handling of foreign particles. This “Guidance on Handling of insoluble Matter and Foreign Particles in APIs” describes in detail

  • the types of particles which can often occur during the manufacture of APIs, API intermediates and raw materials (including packaging materials),
  • suitable measures to minimize the presence of particles or to remove them,
  • how to determine them analytically
  • how to identify the source and to carry out subsequent CAPA measures and an adequate risk management.

This APIC guidance offers valuable assistance for all API manufacturers that are confronted with the problem of the occurrence of foreign particles in their products, intermediates or raw materials. The implementation of the very concrete and practicable recommendations in this guidance offers also valuable supporting arguments for GMP inspections or audits and can help to avoid unpleasant surprises.


///////APIC Guidance,   Handling of Insoluble Matter and Foreign Particles, Manufacture, Active Pharmaceutical Ingredients

Finally published: new Annex 16 on QP Certification and Batch Release

Finally published: new Annex 16 on QP Certification and Batch Release

The European Commission finally has published the new EU-GMP Guideline Annex 16 “Certification by a Qualified Person and Batch Release“.

The European Commission has published the final version of the revised EU-GMP Guideline Annex 16 “Certification by a Qualified Person and Batch Release”. Deadline for coming into operation is 15 April 2016.

As one important topic, it has been pointed out that the major task of a Qualified Person (QP) is the certification of a batch for its release. In this context, the QP must personally ensure the responsibilities listed in chapter 1.6 are fulfilled.  In chapter 1.7 a lot of additional responsibilities are listed which need to be secured by the QP. The work can be delegated and the QP can rely on the respective Quality Management Systems. However “the QP should have on-going assurance that this reliance is well founded” (1.7). Amongst these twenty-one tasks are for example:

  • Starting materials comply and the supply chain is secured, including GMP assessments by third parties
  • The necessary audits have been performed and the audit reports are available
  • Manufacturing and testing performance are compliant with the MA
  • Manufacturing and testing processes are validated
  • Changes have been evaluated and investigations completed

It is important to mention in this context that “the ultimate responsibility for the performance of an authorised medicinal product over its lifetime; its safety, quality and efficacy lies with the marketing authorisation holder (MAH). However “the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force (…), in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP)” (see General Principles).

In the case that the QP has to rely on the correct functioning of the quality management system of other sites, the QP “should ensure that a written final assessment and approval of third party audit reports has been made”. The QP should also “be aware of the outcome of an audit with critical impact on the product quality before certifying the relevant batches.”

Another important section clarifies the role of the QP when it comes to deviations, implementing main features of the EMA Position Paper on QP Discretion (which was issued in February 2006 and updated January 2008). Chapter 3 of the draft describes the “handling of unexpected deviations”. A batch with an unexpected deviation from details contained within the Marketing Authorisation and/or GMP may be certified if a risk assessment is performed, evaluating a “potential impact of the deviation on quality, safety or efficacy of the batch(es) concerned and conclusion that the impact is negligible.” Depending on the outcome of the investigation and the root cause, the submission of a variation to the MA for the continued manufacture of the product might be required.

During the consultation phase, stakeholders expressed their concerns regarding the sampling of imported products. Now the new annex is clear on this: “Samples may either be taken after arrival in the EU, or be taken at the manufacturing site in the third country in accordance with a technically justified approach which is documented within the company’s quality system. (…) Any samples taken outside the EU should be shipped under equivalent transport conditions as the batch that they represent.”

The new annex is rather short on other importation requirements. These requirements will probably be defined in the new Annex 21


.////////////published, new Annex 16, QP Certification and Batch Release

Pharma Regulations for Generic Drug Products in India and US: Case Studies and Future Prospectives

Dr. Suryakanta Swain


The Indian pharmaceutical industry has come a long way from being non-existent before independence to a prominent provider of medicines and health care products in the current decade. The Indian pharmaceutical industry at present is the global leader of growing pharmaceutical manufacturing companies, providing wide range capabilities in the complex field of technology and drug manufacturing. Indian pharma market growing at a rapid pace currently providing Indian pharmaceutical industry third rank all over the world in terms of volume and fourteen ranks, according to market value [1]. The major strength of currently growing Indian pharmaceutical sector is its capability to manufacture wide range of simple analgesic pills to complicated antibiotics, cardiac compounds with peer quality and efficacy and altogether exporting them to developed world. The industry bulk profit comes from exporting generics and API to the developed market mainly US followed by UK, Germany, Brazil etc. The total share of generics accounts in export is 58% providing the major boost, the Indian commerce ministry has set an ambitious export target of $ 25 billion by 2013-14, which can be achieved only by major contribution from generics market [2]. The Indian generics market is growing day by day with Indian pharmaceutical companies seeking more Abbreviated New Drug Application approvals (ANDAs) in US in major segments such as cardiovascular, antibiotics and other groups. The major force for the development of generics market in US came in the form of enacting the Drug Price Competition and Patent Restoration Act of 1984, public law 98-417 better known as “The Hatch- Waxman Act” which created opportunities for developing and marketing generics or better called as abbreviated new drug applications for 180 days. Under ANDAs a pharmaceutical manufacturer can develop and market low price generic version of previously approved innovator drugs, thus providing the same product to patient in pregnable price with safety and efficacy. A generic or biosimilar drug product is one that is comparable to an innovators drug product in dosage form, strength and route of administration, quality, performance characteristics and intended use. All approved products, both innovator and generics, are enlisted in FDA’s orange book. Generic drug application are termed as “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and efficacy instead, generics applicant must demonstrate that there product is bioequivalent (i.e., performs in similar manner to innovator products). India has its unique position all over the world generics market, providing drugs at low cost to the developed world, this is because of its rigid and flexible pharma regulations, patent act which is updated from time to time, thus Indian generics market is playing a major role in growth of Indian economy as it provides a major share in export, mainly exporting generics to US, therefore a proper set of rules and regulations is required in future for producing generics and exporting them, so that Indian pharmaceutical sector and economy maintains its growth and becomes leaders globally.

A Generic Drugs Must:
▪ Contain the same active ingredients as the innovator drug
▪ Be identical in strength, dosage form, and route of administration
▪ Have the same use indications
▪ Be bioequivalent (as a marker for therapeutic interchangeability)
▪ Meet the same batch requirements for identity, strength, purity and quality
▪ Be manufactured under the same strict standards of GMP required for innovator  products
Table 1: Regulatory requirements for generic drugs.

Pharma Regulations for Generic Product in India and US

Generics have an important role to play in public health as they are well known to medical community and usually more affordable due to competition. They are formulated when patent and other exclusivity rights expire. The key for generic medicines is their therapeutic interchangeability with originator products. To ensure the therapeutic efficacy generic products must be pharmaceutically interchangeable (contain the same amount of active ingredient and have the same dosage form) and bioequivalent to the originator product. Bioequivalence is usually established using comparative in-vivo pharmacokinetic studies with originator products. The detailed description how it is carried out is described in respective WHO document and national regulatory guidelines. Well resourced regulatory authorities require that a generic medicine must meet certain regulatory criteria [3,4]. The major regulatory requirement for generic drug is presented in Table 1. For applying the ANDA’s in US, application is submitted under any of the below subsections of 505(j) of Federal act, it is important to comply with rule and regulations of US because it’s the major export destination for Indian generics manufacturers [5], the various application which can be applied for ANDAs in US is depicted in Table 2. The ANDAs review process is most important for developing generics, the review by FDA and CDER is done for generic applicant to compare its therapeutic bioequivalent with brand drugs after its approval for equivalency generic version of drug can be marketed (Figure 1). The review for equivalency is done by taking into account the bioavailability of product with branded drug, its microbiology, chemistry and labeling of product, this are current regulation to follow for generic approvals given by respective FDA.

Subsection of 505(J) Products Type
Paragraph I For the products for which no patent information is available in the orange book.
Paragraph II Used for the products for which all the applicable patents are expired
Paragraph III Used for the products for which the some or all the applicable patents are valid and the applicant confirms that the product will not be placed in the market till such patents are expired.
Paragraph IV Used for the products for which some or all the applicable patents are valid and applicant try to file the product which does not infringe those patents or applicant invalidates the granted patents. On successful outcome the generic applicant enjoys the six month exclusivity in the market.
Table 2: Different types of ANDA applications in US.
Figure 1: Explain the ANDA reviews process for development of generic drugs.

Future Generic Products in India and US

It is seen that there is an upward swing in the generic market. It has reached 100 billion dollars in the past and is estimated to be three times higher than the overall growth of drugs. The current trend exhibits that blockbuster drugs are scheduled to lose their patent protection, opening the doors to cheaper generic drugs between 2013 and 2015 with the total market value in billions. It is expected that the percentage of generic drugs in the US market will rise from 14 to 21. This growth will enhance the export prospect of India and it will be doubled every year. It will be due to increase in the number of low cost workers and degree of innovation. Recent success in track record in design operation of high tech manufacturing, testing, quality control, research, clinical testing and biotechnology also contribute to this higher growth. Indian pharmaceutical industries those who have USFDA (United States Food and Drug Administration) affiliations and approval of ANDA (Abbreviated New Drug Applications) will stand benefited. Now India’s global share in the field of generic market is stipulated at 35% which is very high [6,7]. Table 3 describes list of various drugs going to get off-patent in 2015. To make the situation more favorable the Indian government has also introduced scheme of providing generic drugs to patient in hospitals with various Jan-aushadhi Kendra (Facilitation Centre). Thus future prospects of generics in India and US are very high as they are the next big thing in health care scenario. Consistent with prior research, MEPs (Market Exclusivity Periods) for drugs experiencing initial generic entry in 2011-2012 was 12.6 years for New Molecular Entities (NMEs) with sales greater than $100 million in the year prior to generic entry, and 12.9 years for all NMEs. Further research may reveal variation by type of NME, whether defined by molecule type or other classification. Generic competition has intensified over the past 10-15 years, and the MEP has become an even more important indicator of the economics of brand-name drugs. The MEP is critical to manufacturers’ ability to earn profits on brand-name drugs to fund future research and development activities, and brand-name drug shares rapidly drop following initial generic entry. Over 80% of brandname drugs experiencing initial generic entry in 2012 had faced at least one Paragraph IV patent challenge from a generic manufacturer, up from only 9% for drugs experiencing initial generic entry in 1995. These challenges are filed relatively early in the brand drug life cycle, on average within 7 years of brand launch. Developments for the generic pharmaceutical industry are encouraging as more brand-name drugs come off patent and payers push for cost cuts in health care. In addition, due to increasing FDA budget and staffing should begin to cut the backlog of branded and generic drug applications and increase the ability of the FDA to inspect facilities here and overseas as generic biologics get to market in the next few years [8].

Sl. No. Name of the Drug Category Patent Holder Expiry Year
1 Eletriptan Migraine Merck August, 2013
2 Teriparatide Hormone Eli Lilly July, 2013
3 ImatinibMesylate Oncology Novartis May, 2013
4 Insulin Lispro Diabetes Eli Lilly May, 2013
5 Linezolid Antibiotic Pharmacia Nov, 2014
6 Transtuzumab Biopharm Gentech Oct, 2014
7 Posaconazole Antibiotic Shering Aug, 2014
8 Omalizumb Respiratory Roche Feb, 2015
9 Telethromycin Antibiotic Aventis April, 2015
10 Alemtuzumb Oncology Millennium Dec, 2015
Table 3: List of some important drugs going to be off-patents

Upcoming Challenges for Indian Generics Manufacturers in Global Market

The generic drug companies in India have broad technological and diversified market capabilities. As more and more patents expire, the generic portion of the pharmaceutical market is expected to continue to have increased sales. The scientific capability for manufacturing and supplying generic drugs of these companies will give them an edge over others and make them major players in the international generics market. Fortunately India has the best subject skills to galvanize foreign investors. The encouraging scenario of basic research and drug discovery will also support the changed dynamics. But their future sustainable growth depends on sustaining in competitive markets of developed world. The major challenges for generic manufactures are strengthening the existing regulatory system especially for enabling more detailed and universal classification of drugs and chemicals between branded generic and generics. High R&D cost and investment in research is also a major stumbling block in this direction [9].

Generic  Name Generic Manufacturer Brand Name Approval Date Year Of Exclusivity Rights Expire
Pioglitazone Hydrochloride and Glimepiride Tablets, 30 Mg/2 Mg and 30 Mg/4 Mg Takeda Pharms USA Duetact Tablets Jul 28, 2006 2027
Fexofenadine Hydrochloride Orally Disintegrating Capsules or  oral: 60 Mg Sanofi Aventis USA Children’s Allegra Allergy & Allegra Hives Jul 25, 1996 May 26, 2014
Mupirocin Calcium, Cream; topical Glaxosmithkline Bactroban Cream Dec 11, 1997 Oct 29, 2013
Doxorubicin Hydrochloride Liposome Injectable, Liposomal; Injection 2 mg/ml Janssen Res And Dev Doxil Liposome Injection Nov 17, 1995 May 17, 2014
Zoledronic Acid Injection, 4 Mg (Base)/5 Ml; Packaged In Single-Dose Vials Novartis Zometa Injection Jun 17, 2011 2031
Esomeprazole sodium – injectable;intravenous (Eq 20mg base/vial) Astrazeneca Nexium I.V. For Injection March 31, 2005 2025
Amlodipine besylate; hydrochlorothiazide; valsartan – tablet; oral (5Mg;12.5Mg;160Mg) Novartis ExforgeTablets April 30, 2009 2029
Table 4: Describes list of various new ANDAs approval in the year 2013.

Amendments in the Pharma Regulations for Generic Products

The Hatch-Waxman Act enacted 1984 is a landmark act. It allows generic drugs to enter the market without repeating expensive clinical trials required for their branded drugs. The legislation is meant for balancing the world of generic and branded drug industries. It provides accessibility to lower-cost generic drugs while still encouraging innovation and development of new drugs. Nevertheless, the legislation created unintended legal barriers that have slowed the entry of generic drugs into the market due to significant legal loopholes. The generic drug companies are allowed to market the drug after the patent and certain exclusivities expire. It has led to the prolific growth of generic drugs in the market. Thus some changes are required so that the loopholes can be filled and the regulation can be strengthened and selling of low cost drugs can be achieved. The change in rule related to alleged abuse of the 30-months stay provision is to be taken care were the ANDA applicant informs the original patent holder about the generic version filing, where they have 45 days to file a patent infringement suit against the generic applicant. If an infringement suit is filed within the 45-days period, FDA approval to market the generic version is automatically postponed for 30 months. These stays are extremely advantageous to innovating companies, because they provide over 2 years of additional market sales. Company takes profit by utilizing this route and delays the entry of generic drug in market; many steps have been taken by amending act of Greater Access to Affordable Pharmaceuticals Act passed in 2003 by American government. Extending the extensions by alleged abuse of the 30-month stay provision is done by many companies that holds patent, the companies are able to further delay the market entry of generic drugs is through multiple patent listings in the Orange Book, which is the FDA’s official listing of all the approved products. There are instances in which brand-name companies listed related patents in the Orange Book after an ANDA had already been filed by a generic manufacturer. The effect of these “later-listings” is that the generic applicant is then required to re-certify that the laterlisted patent is also invalid or not infringed and notify the patent holder of the re-certification. Thus more delay occurs in generic drug to reach market [10]( Figure 2).

Recent Cases and Incidents of Generic Products Regulation in India and US

The future prospects of generic product regulation in India and US are of great importance as they will decide the direction of growth of Indian Pharmaceutical Industries. Based on the recent cases and incidents that have occurred in India and US related to the generic product utilization, the new crucial roles will be implemented. The list of a few recent cases and incidents that happened in connection with generics in India & US are discussed in detail below (Figure 3).

Figure 2: Schematic overview for the benefits of Hatch-Waxman Act.
Figure 3: Steps for the launching of generic drugs

The Karen L. Bartlett case

In December-2004, Physician of Karen L. Bartlett was prescribed Clinoril, the brand-name version of the Non-Steroidal Anti- Inflammatory Drug (NSAID) sulindac, for shoulder pain of Karen L. Bartlett. Her pharmacist dispensed a generic form of sulindac manufactured by petitioner Mutual Pharmaceutical. Karen L. Bartlett soon developed an acute case of toxic epidermal necrolysis. She is severely disfigured, has physical disabilities, and is nearly blind. At the time of the prescription, sulindacs label did not specifically refer to toxic epidermal necrolysis. By 2005, however, the FDA had recommended changing all NSAID labeling to contain a more explicit toxic epidermal necrolysis warning. Respondent sued Mutualin New Hampshire state court. A jury found Mutual liable on respondent’s design-defect claim and awarded her over $21 million. The First Circuit gets ratified. As relevant, it found that neither the FDCA nor the FDA’s regulations pre-empted respondent’s design-defect claim. It distinguished PLIVA, Inc. v. Mensing, 564 U.S in which the Court held that failure-to-warn claims against generic manufacturers are pre-empted by the FDCA’s prohibition on changes to generic drug labels by arguing that generic manufacturers facing design-defect claims could comply with both federal and state law simply by choosing not to make the drug at all. This case is being closely watched by pharmaceutical companies, federal regulators and others, the Supreme Court will decide on whether Mutual can be held responsible for Ms. Bartlett’s injuries. The outcome is likely to further clarify the legal recourse for patients who take generic drugs, which now account for 80 percent of all prescriptions in the US. The verdict on both the sides will be playing a crucial role in drafting future pharma regulations as if the court agrees with Mutual and rules that generic companies cannot be sued for defective products, trial lawyers warn that patients will be left with very few options if they are injured by a generic drug whereas manufacturers of generic drugs and other business groups have said that if the court sides with Ms. Bartlett, the decisions of individual juries could trump the authority of federal agencies like the Food and Drug Administration and potentially lead drug makers to remove valuable medicines from the market. Thus this case will be important for the future of generics drug market in US and India [11,12].

Pay to delay pharmaceutical case

The question of whether the manufacturer of a branded drug can pay another drug manufacturer to keep a generic version of the drug off the market was heard by the United States Supreme Court on 25th March, 2013. The court will decide whether “pay-to-delay” or reverse settlements arrangements, in which the manufacturer of a branded medication pays another company to keep a generic version off the market, are legal or not, the outcome of the case is very important because it will decide for how many patients pay for medications. Federal Trade Commission challenges the payments. It sees these arrangements as collusion, design to stop competition in the market place and is meant for violation of antitrust laws of the nations. The drug makers, in contrast, see the settlements as a routine way of settling a legal dispute, with each side getting something it wants. The Hatch- Waxman Act 1984 has some loophole. Payments are made possible by using these loopholes. Certain amendments are made in the last decade to encourage generic manufacturers to challenge patents held by branded manufacturers before they are set to expire. Typically, the generic manufacturer files for FDA approval to market a generic version of a branded medication that is still under patent protection, and the branded manufacturer sues the generic manufacturer for patent infringement. An increasing number of such cases end in “payto- delay” agreements according to which the generic manufacturer agrees to hold off on introducing the generic version in exchange for payment from the branded manufacturer. The case in point is Androgen (testosterone gel), produced by Solvay Pharmaceuticals whose patent is set to expire in 2020. The bone of contention between Actavis (formerly Watson Pharmaceuticals) and Solvay Pharmaceuticals was Andro Gel. Actavis filed for FDA approval to market a generic version of Andro Gel in 2003, and Solvay sued. In 2006, the FDA approved the generic version for marketing of Actavis, but the suit remained status quo. Later in 2006, the companies came to a settlement according to which Solvay would pay Actavis $20 to $30 million per year in exchange for help with marketing and an agreement to keep its generic version of Andro Gel off the market until 2015. The FTC (Federal Trade Commission) contends that the drug companies colluded to maintain Solvay’s monopoly on Andro Gel because, without the settlement, the generic version would have become available in 2006. A federal district court dismissed the FTC’s argument in this case, but another district court in a similar case decided the opposite way, so it is now up to the Supreme Court to decide and decision is expected. Moreover the best verdict according to many experienced federal judges that supreme court should not generalize the law, where as it should be implemented on case to case basis, thus this case should be great importance for Pharma regulators to draw guidelines for future regulations of generics in India and US and it will be important for patients to decide whether they will opt for cheaper or expensive medicines [13,14].

The Ranbaxy saga case

The criminal fraud that Ranbaxy has done with US FDA has let down many but it’s the fellow generics drug maker of India that will face the heat, this will be a very important incident which will decide fate of generics drug market of India in US and its regulation. Ranbaxy pharmaceutical of India is charged with producing low quality generic drugs in US and manipulating data’s required for filing NDA and ANDA approvals in US, thus cheating their counter parts in many ways to be first in the race of producing generic version. Ranbaxy pleaded guilty to seven federal criminal counts of selling adulterated drugs with intent to defraud, failing to report that its drugs did not meet specifications, and making intentionally false statements to the government. Ranbaxy agreed to pay $500 million in fines, forfeitures, and penalties-the most ever levied against a generic-drug company. The company, now majority owned by Japanese drug maker Daiichi Sankyo, sells its products in more than 150 countries and has 14,600 employees. It also came to light that even Ranbaxy scientist adulterated there generic testing drug with branded drugs for manipulating bioequivalence study.

Thus these serious allegations on one of the top India pharmaceutical company could be a major setback for generic manufactures and Indian Pharma regulator as they have failed to, therefore some strict regulations could be implemented by US FDA in future for Indian generics producers which could be a serious issue as it will lead to effect the generics drug market in India. Thus this will be the major factor which will decide the fate of future regulation of generics in India and US [15,16].

Miscellaneous cases and incidents

The study discusses the case of Swiss drug maker Novartis plea overruled recently by the Supreme Court was an attempt to win patent protection for its cancer drug Glivec. This was a serious blow to Western pharmaceutical firms who are increasingly focusing on India to drive sales and it also affects Indian and US generic market. Glivec (ß-polymorphic form of imatinib mesylate) is indicated for treatment of certain blood and stomach cancers. The Supreme Court decision implies that a clutch of Indian companies, including Cipla, Ranbaxy and Natco, could continue marketing generic versions of the drug at a fraction of the cost of Novartis’ product. While Novartis’ Glivec costs over one lakh a month, local companies sell versions of the drug at roughly ten thousand a month. Supreme Court’s ruling states that the drug has failed in “both the tests of invention and patentability” under Indian law. On the other hand, Glivec is widely recognized as one of the most important medical discoveries in decades, but it lost the battle on innovative quality grounds. The verdict can be interpreted as a battle between research and innovation on one side and public health and affordability on the other. It is true that the prospect of producing cheaper generic versions of lifesaving drugs in the country, thus sale of generics will increase and generic market will be boosted up. Thus the case study suggests that the future of generics in India is bright and this case will be a benchmark for it. The well documented Novartis case in the ‘Glivec’ matter has brought the Indian patent system into sharp focus, whereas Indian regulatory authority should reform new rules for granting patent so that bigger MNCs should be attracted to India in future for better business [1820].

Recent patents

With expiration of patent branded drugs are applied for generics version, some of the new ANDAs approval in year 2013 [17] are described briefly in Table 4.


In situations where demand for medicines exceeds supply, and cost effective drug in demand with minimum expenditure, generic drug are best choice fulfilling this demand. The current and future prospective of generics in India and US is very bright as Indian government looking towards generic drugs for providing better health care to public. Indian pharmaceutical industries grow rapidly all over the world and one of largest generic exporter in world where as, US being the major destination for export. Thus, the proper validated regulation is required for manufacturing generic drugs in India and US which requires proper symbiotic relation between India and US. Some amendments are warranted in Hatch Waxman Act 1984 for developing generic drug in better way, where as re-election of Barack Obama in US provides positive increase in generic market as his government extending health care insurance for additional 30 million Americans in the health care ambit, creating increased demand for generics.


Pharma Regulations for Generic Drug Products in India and US: Case Studies and Future Prospectives

Suryakanta Swain*, Ankita Dey, Chinam Niranjan Patra and Muddana Eswara Bhanoji Rao

Roland Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Berhampur, Odisha, India

Suryakanta Swain
Assistant Professor
Roland Institute of Pharmaceutical Sciences
Department of Pharmaceutics
P.O.: Khodasingi, Berhampur-7600 10, Odisha, India
Tel: 91-943-803-8643; 909-037-4275
E-mail: swain_suryakant@yahoo.co.in

Citation: Swain S, Dey A, Patra CN, Bhanoji Rao ME (2014) Pharma Regulations for Generic Drug Products in India and US: Case Studies and Future Prospectives. Pharmaceut Reg Affairs 3:119. doi: 10.4172/2167-7689.1000119

Suryakanta Swain
Asst. Professor-cum-Placement Officer
Department of Pharmaceutics at Roland Institute of Pharmaceutical Sciences

Dr. Suryakanta Swain was born on 8th June 1980 in Debendrapur, Balasore, Odisha (INDIA). After completing his B. Pharm with 79.37% from Berhampur University, Odisha, India and join in to M. Pharm (Pharmaceutics) by qualifying GATE and N.I.P.E.R with All India entrance examinations with C.G.P.A 8.89 from Biju Patnaik University of Technology, Rourkela, Odisha, India. He is completed his Ph.D in Pharmacy from Berhampur University on 09.12.2013. He started his career as a Research Trainee Executive in Formulation Research & Development in Medley Pharmaceuticals Pvt. Ltd, Daman, India. Presently he is working as Asst. Professor-cum-Placement Officer in Department of Pharmaceutics at Roland Institute of Pharmaceutical Sciences, Berhampur, Odisha, India. So far he has published thirty articles of reputed national & international journals with high indexing or impact factor. He has edited one book, authored four books & one book chapter an international level. He has filled One Indian patent. He has permanent Editor, Advisary, Editorial board members and reviewers in more than 15 national & international journals.
Research Interest
Mucoadhesive DDS, Transdermal DDS, Liposomal DDS, Selfemulsifying DDS, Micro and Nanoparticulate DDS, Gastro-Intestinal DDS, Colon Specific DDS and Controlled DDS.
Solid Lipid Nanoparticle: An Overview
Suryakanta Swain and Sitty Manohar Babu
Editorial: Pharmaceut Reg Affairs 2015, 4: e154
doi: 10.4172/2167-7689.1000e154
Pharmaceutical Impurities and Degradation Products: An Overview
Prafulla Kumar Sahu, Suryakanta Swain and Manohar Babu S
Editorial: Pharmaceut Reg Affairs 2015, 4: e146
doi: 10.4172/2167-7689.1000e146
Impact of Pharmacovigilance in Healthcare System: Regulatory Perspective
Suryakanta Swain and Chinam Niranjan Patra
Editorial: Pharmaceut Reg Affairs 2014, 3: e143
doi: 10.4172/2167-7689.1000e143
Bio-Relevant and Bioequivalence Studies: An Overview
Suryakanta Swain and Nerella Nagadivya
Editorial: Pharmaceut Reg Affairs 2014, 3: e140
doi: 10.4172/2167-7689.1000e140

Roland Institute of Pharmaceutical Sciences, Department of Pharmaceutics, Berhampur, Odisha, India

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FDA Inspections at API Manufacturers – current Warning Letter Trends

The Warning Letters the FDA sent to active ingredient manufacturers last fiscal year, show similar patterns. Find out more about the frequent deficiencies found in the area of responsibility of quality assurance and in the handling of electronic data in production facilities for active pharmaceutical ingredients.


Taking a look at the Warning Letters the FDA issued after inspections of activesubstance manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking that only non-American companies are among the addressees. Almost half of them are Indian companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL); Thailand (1 WL); Czech Republic (1 WL).

The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or missing data integrity. Each of the 8 warning letters contains the following comment in the same wording:

“Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.”

The lack of access control on electronic (raw) data is an issue the FDA investigators have been observing for a long time, especially during inspections in pharmaceutical companies. In this as well as in the last fiscal year there were significant deficiencies in several companies – medicinal product as well as API manufacturers – as the comments in the appropriate Warning Letters show. For more information also see the GMP news Another FDA Warning Letter with Focus on “Data Integrity” and FDA Warning Letter on Data Integrity.

Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also affects other areas. In the Warning Letters, the following examples can be found for this:

  • “Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.”
    “Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.”
    Data were manipulated by laboratory staff (change of the file name), to fake results from identity tests in batches which in reality were not performed. Quality assurance was not able to uncover this manipulation.
    Despite an unknown peak in the examination for residual solvents the relevant batches were released. Upon receipt of a complaint regarding this peak an examination was conducted with the result that the contamination originated in the production process itself. Preventive control measures to avoid this contamination were not established.
  • “Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected.”
    As a result of a complaint (bad smell), a cause study was initiated which was completed prior to implementation of the preventive measures again. The CAPA measures subsequently carried out were obviously not associated with the reason for the complaint.
  • “Failure to have appropriate controls for issuance of batch records”.
    The use of document templates for batch records is out of control. These can be printed out from the production staff’s personal computers. Although there is an SOP for the control of batch records there are no appropriate training records.
  • “Failure to have appropriate documentation and record controls.”
    Data for tracing raw materials are not available. Log entries are without date/visa and partly corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this was not trained.
  • “Failure to record activities at the time they are performed and destruction of original records.”
    Original records of critical process data on uncontrolled memos were transferred subsequently in new report templates (after batch approvals) and then destroyed.

This selection of examples shows the lack of fundamental GMP principles which leads to a blatant misconduct of staff and ultimately to quality defects in the final product. The main responsibility usually has the quality unit, which task it actually would be to ensure a thorough training in production and quality control and to monitor compliance with the appropriate regulations. These examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there are very similar findings in Warning Letters issued to medicinal product manufacturers. An analysis of these Warning Letters issued in the fiscal year 2015 will be part of one the coming newsletters.

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New FDA Requirements for the Development of Herbal Medicinal Products

The previous FDA guideline for herbal medicinal products from 2004 is supposed to be replaced by a new version. In August 2015, the FDA has presented the draft of the revised guideline. Find out more about the FDA Guideline Botanical Drug Development.


In August 2015, the FDA has published a draft of the guideline “Botanical Drug Development”. This guideline addresses issues arising from the particular nature of herbal medicinal products. After its finalization it is supposed to replace the previous guideline from June 2004.

The general approach in the development of herbal medicinal products remained unchanged since 2004. But due to the better understanding of herbal medicinal products and the experience gained during the review of the approval documents for herbals (NDAs/New Drug Applications and INDs/Investigational New Drug Applications), specific recommendations could be adjusted. Still, new sections will be supplemented to better address the late development phase.

The draft guideline also covers the following topics:

  • General, regulatory requirements
  • INDs for phase 1-3 clinical trials
  • NDAs for herbal medicinal products

For further information please see the full FDA document ‘Botanical Drug Development’.

Genotoxic impurities: the new ICH M7 addendum to calculation of compound-specific acceptable intakes

Genotoxic impurities: the new ICH M7 addendum to calculation of compound-specific acceptable intakes

The draft for a guideline ICH M7(R1) published recently supplements the ICH-M7 guideline published last year. Read more about the calculation of compound-specific acceptable intakes of genotoxic impurities.

The final document of the ICH-Guideline M7 was published in June 2014. It describes the procedure for evaluating the genotoxic potential of impurities in medicinal products (see also our news Final ICH M7 Guideline on Genotoxic Impurities published dated 23 July 2014).

An important approach to the risk characterisation of impurities is the TTC concept (TTC = threshold of toxicological concern). According to this approach the exposure to a mutagenic impurity having the concentration of 1.5 µg per adult person per day is considered to be associated with a negligible risk. It can be used as default evaluation approach to most pharmaceuticals for long-term treatment (> 10 years) and where no carcinogenicity data are available (classes 2 and 3). According to ICH M7 the TTC concept should not be used where sufficient carcinogenicity data exist. Instead the data should be used to calculate or derive compound-specific acceptable intakes.

Now the ICH published an addendum to Guideline M7 with the title “Application of the principles of the ICH M7 Guideline to calculation of compound-specific acceptable intakes” (“Addendum to ICH M7”; short name “M7(R1)”).

This addendum describes the basis for calculating the acceptable intakes for 15 substances in total that are common and widespread in pharmaceutical manufacturing. These substances are known to have mutagenic/carcinogenic potential (ICH M7(R1) contains comprehensive references on the toxicology of these substances). The calculations of the AI (acceptable intake) or PDE (permitted daily exposure) values are partly based on a linear extrapolation from the TD50 values as well as on toxicological data on the non-linear dose-response curve of the relevant substances.

ICH M7(R1) has the status of a draft consensus guideline (step 2 document). The draft guideline was published on the EMA “Scientific Guidelines” site as step 2b document on 4 August 2015 for consultation (deadline for comments: 3 February 2016)