CMC Resources

Improvements and Updates to the FDA Inactive Ingredient Database

Improvements and Updates to the FDA Inactive Ingredient Database The FDA recently announced it has made corrections, updates, and additions of a backlog of formulations to the Inactive Ingredient Database (IID), an important modification for drug developers and development. The previous state of the IID had become an issue as excipient suppliers recommend the use […]
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How Much Is a First Cycle Review ANDA Approval Worth to You?

At the recent GPhA meeting in Orlando, Florida, Dr. Kathleen Uhl from the FDA Office of Generic Drugs (OGD) spoke about the quality of Abbreviated New Drug Application (ANDA) submissions and highlighted the detriments of a poor quality submission. All would agree that a poor quality submission is costly for drug product development. Dr. Uhl […]
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Quality Metrics – Coming Soon to Your Manufacturing Facility

In the July 28th, Federal Register, (Under “Meetings”) FDA announced the availability of the draft guidance “Request for Quality Metrics-Guidance for Industry.” Although there are “requests” for quality metrics in the guidance, the bulk of the document tells industry what quality metrics they will be reporting, at least initially. FDA primarily cites Sections 706 and […]
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Use of Extrusion-Enabled Pharmaceutical Processes in Drug Development via a Streamlined Regulatory Pathway

Extrusion-enabled pharmaceutical processing (E2P2) has long been employed in pharmaceutical development (Drug Development and Industrial Pharmacy. 33:909-926,1043-1057 (2007)). Reasons for utilizing E2P2 include: Enhancing physico-chemical properties of APIs such as solubility and stability Modifying in vivo release of a drug to enhance bioavailability and clinical efficacy Facilitating development and manufacture of fixed combination drug products […]
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Manufacturing Support for “Breakthrough Therapy” Designation for Solid Oral Dosage Forms

In November, this author participated in an open forum at the AAPS Annual Meeting focused on streamlining manufacturing and scale up to support ‘breakthrough therapy’ designation for solid oral dosage forms. The goal was to provide clarity for breakthrough therapies and chemistry, manufacturing and controls (CMC) challenges to develop a quality submission in a shortened timeframe where […]
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2013 505(b)(2) NDA Approvals

2013 appears to be a challenging year for FDA NDA approvals.  FDA’s John Jenkins reviewed the  NME NDA and BLA approvals through November 2013, showing that 25 such products were approved (see chart below).  These 25 approvals are 505(b)(1)NDA and BLA’s.  Generally, this performance was seen as disappointing, but readers of this blog know that the number […]
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Expensive, cheap, value? CMO costs.

Contract manufacturing organization (CMO) A bids $600,000.  CMO B bids $450,000.  Which bid is cheaper? Assume for the moment that both CMOs provide equal service parameters: skill, capacity, timelines, regulatory history, experience, etc. and we are judging both based only on price. No, this is a not trick question.  But the result is not obvious. Even with a detailed […]
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New Generic Stability Requirements

After much delay, FDA just released the new Guidance on the stability requirements to file and obtain approval of a generic drug product and API under 505j.  The new requirements bring ANDAs closer in line with NDAs and ICH.  The new requirements as summarized in the Guidance are: 1. Submit data from three pilot scale batches […]
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K-V Pharma bankrupt – Claims FDA Doesn’t Back Makena

K-V Pharmaceuticals filed for Chapter 11 bankruptcy. After years of GMP issues narrowed the product offering to just one product, Makena (17-hydoxyprogesterone caproate), poor sales of the product couldn’t sustain the company. In this blog I have discussed the filing and approval of Makena, a product for pre-term labor.  Prior to this approval, the product had been available […]
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Drug Development Planned Like the Titanic

How many drug development companies leave it up to the CRO or CMO to design or execute their studies or formulation/manufacturing without oversight?   Like those who boarded the Titantic 100 years ago, they seem to trust the mantra that their contractor’s work is unsinkable.  MAP Pharmaceuticals seemed to do just that – the approval of their […]
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Stability Changes coming to ANDAs

This post comes from D.C. where I am attending the GPhA Fall Technical Conference.  We just completed a presentation by FDA’s Glen Smith.  He  detailed the proposed new stability requirements for ANDA drug products.  It is essentially the adoption of ICH Q1A.  For readers of this blog, we know that 505(b(2) NDA’s must have 12 months […]
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Mitosol – an Orphan & 505(b)(2) without clinical studies

Mobius Therapeutics announced that it has received orphan drug status for Mitosol to prevent the recurrence of pterygium after surgical excision. The active ingredient, mitomycin has been used without FDA approval for eye surgeries since the mid 1960’s. Due to its long history of use, the FDA did not require that Mobius conduct clinical trials. […]
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Injectables: 505j or 505(b)(2)?

Generic injectable drug products are treated differently than other routes of administration when it comes to permitted differences from the RLD. For most dosage forms, the sponsor is allowed to change excipients as long as the test product is bioequivalent to the RLD. No so for injectables, the excipients must be the same. If the […]
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Why have a Quality Overall Summary for the Quality Module?

The Quality Module (Module 3 or Chemistry, Manufacturing and, Controls section (CMC)) in the eCTD format serves as the backbone of any regulatory submission, an IND or NDA. We have discussed this in a previous blog posting. There is debate about the usefulness of the Quality Overall Summary (QOS or Module 2.3 of eCTD) with […]
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India Tightening Inspections on Raw Materials

Cheaper is not always better. The cost of drug development demands that the pharmaceutical industry review the cost of all components of the program. In doing this, often the choice of the active pharmaceutical ingredient (API) manufacturer is driven by cost. Many of the API’s and raw materials are now coming from China. Any company […]
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Labeling for Abuse-Deterrent Drugs

This past Tuesday (6/8/2010), we participated in a DIA-sponsored webinar entitled Understanding the Development and Label Allowances for 505(b)(2) Abuse-Deterrent Products. Joining me, Ruth Stevens our CSO and Cindy Phurrough, our Clinical Operations head, was Dr. Lynn Webster, Chief Medical Officer of Lifetree Clinical Research and Pain Clinic. Ruth reviewed the regulatory background, the types […]
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Target Product Profile

Today’s blog courtesy of Lynn Gold, Ph.D. Camargo’s VP of CMC. In any project development program an understanding of the program goal is critical to finding the shortest path to the final result. Generation of a Target Product Profile early in a development program facilitates reaching the goal of a marketed drug product. It provides […]
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CMC Issues Again

Several previous blogs have discussed the importance of maintaining quality oversight of a contract facility to the drug development timeline. Below is an example of a generic manufacturer with problems maintaining quality oversight of its own multiple sites. Apotex, the Canadian generic manufacturer received a CMC based warning letter on March 29th. This recent warning […]
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Manufacturing Problems for Intravenous Emulsions

Many of the drug products manufactured by Hospira, including intravenous nutritional emulsions and propofol have been on the market for years. Hospira received a warning letter on April 12th citing two of its intravenous drug product manufacturing plants in North Carolina. The sites were inspected by the FDA in April 2009, and the violations cited […]
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Do Not Neglect Your Third-Party Drug Substance Manufacturer

Another example of the importance CMC was reported in January. Warner Chilcott plc received a complete response letter from the FDA. The “low dose” oral contraceptive NDA was the file in question. The FDA inspection of the third-party drug substance manufacturing facility and control testing laboratory used to support the application reported outstanding deficiencies which […]
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Can and Should ANDA Labeling Differ from the RLD?

In the past two months, two appellate courts, the Fifth Circuit and the Eighth Circuit have handed down decisions which essentially state that generic pharmaceutical companies can be sued in state courts for failure-to-warn regarding serious side effects, where the generic companies had conformed their labeling to that of the current Reference Listed Drug. For […]
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Analytical Requirements for Oral Solutions

Analytical requirements for the NDA submission of an oral solution to the FDA are very similar to those requirements for any new drug product. The analytical methods that are used for the testing of an oral solution at the NDA stage of development should be fully validated per the ICH guidelines, Q2A and Q2B, now […]
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Start Your New Year Right

Do not start the New Year off with CMC issues. Take the time to follow-up on your subcontractors before the FDA finds problems and delays submission approval. Pharmaxis Ltd. just found out the hard way that poor oversight of manufacturing and testing subcontractors will be a concern for the FDA. This concern translates into approval […]
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505(b)(2) For Formulation Changes

A couple of weeks ago I was invited to present at the 2009 Nebraska Research and Innovation Conference.  The theme of my talk was “The Case for Improving Existing Drugs”. There are several factors driving people to the 505(b)(2) development pathway, a couple of which are: Generic cliff.  By about 2017 there will be very […]
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Comparability Protocols

What do you need to do when you need to change suppliers or manufacturing sites?  Among the many choices is a formal FDA Comparability Protocol.  Our VP CMC, Lynn Gold explains. Advance planning can improve the possibility of FDA accepting your proposed change. One alternative that can streamline the process of change and add clarity to the requirements […]
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Test Specifications for Stability Studies

Pivotal stability programs that are used to generate stability data for NDA submissions are different than research stability programs used to design the drug product, explore packaging configurations, etc.  This is common sense, but we have seen instances of pivotal stability programs that have been performed for clients with no defined specifications.  A stability protocol […]
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FDA requests melamine testing of ingredients

U. S. government officials both inside and outside of FDA have acknowledged that the Agency currently lacks the resources, both financial and human, to adequately monitor the materials going into products being used in the United States.  The answer?  In the case of the somewhat notorious contaminant melamine, the answer is to make regulated industry […]
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Benzyl Alcohol- NME approved under 505(b)(2)

The source of NMEs (new molecular entities) for use in 505(b)(2) drug development programs is vast.  A major benefit of an NME is the 5 year data exclusivity. Sciele Pharma recently (4/9/09) obtained 505(b)(2) approval for a 5% benzyl alcohol lotion for the treatment of head lice in patients 6 months of age and older.  Benzyl alcohol is […]
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Multiple Dosage Strength Products – CMC Considerations

Developing a product with multiple strengths?  How do you go about filing multiple strengths in an IND?  Lynn Gold, Ph.D., Camargo VP of CMC explains: How and when to draft one CMC section covering multiple drug strengths for the same dosage form? Long-term drug development goals may include multiple strengths of a drug product to support […]
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Botanicals: What is the starting material for the API?

We typically work with small molecules of synthetic origin, but occasionally are retained to work with products that have active ingredients from botanical (plant) sources.  Lynn Gold, our VP of CMC provides the following discussion on how to define the starting material for the Active Pharmaceutical Ingredient (API). The definition of the starting material for any API is […]
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One vs. Two batches for single-dose and multiple dose studies

Today’s posting stems from a client question.  The client’s product candidate is an oral product that requires both single- and multiple dose pharmacokinetic studies. Question:  Do companies ever use one pivotal batch for single-dose (SD) study and another batch for the multi-dose (MD) study?  What are the pros and cons of doing this? See the […]
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CMC Bridging Studies

We have discussed bridging studies in this blog before in the context of the phase 1 bridging study to link the safety and efficacy of the RLD to the proposed drig product.  So, what is meant by a bridging study for CMC* purposes?During the 505(b)(2) drug development process we often change the formulation, components or API. […]
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505(b)(2) NDA Labeling

All NDA submissions require that a draft label be included. For a 505(b)(2) NDA, where do you get the information for this label? What labeling is required? What is labeling?  Well, the “label” is what is on the immediate container of the drug product and can contain printed or graphic information.  “Labeling” is all other […]
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What is a ‘483?

You may read in the news or a company press release that a manufacturing site has received a ‘483.  This is usually considered bad news. Indeed, failure to remedy observations in a ‘483 can lead to withheld product approvals or even plant closure. When the FDA makes a visit to inspect a facility (manufacturer, lab, […]
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Indevus’ Stock drops 70% on FDA’s request for more safety data

On June 4, Indevus Pharmaceuticals reported that the FDA is likely to request additional safety data before approving NEBIDO®, its depot testosterone product for the treatment of male hypogonadism.  The news sent the stock on a  tumble – losing $2.46 to $1.26/share (a 70% decline) in the subsequent trading period (it has since recovered a bit, Friday’s […]
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NanoNews – Beads deliver drug to site of action

In another fine example of a formulation change, Biocompatibles International reported that its very small beads were used to sequester Doxorubicin (adriamycin).  The resulting beads were delivered via a catheter directly into the liver of patients with liver tumors.  The tumor growth was suppressed for long enough in 12 of 18 patients to receive a […]
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505(b)(2) – Part 2: The Assessment: CMC Development Plan

CMC Development Plan All too often we see plans that don’t integrate the clinical trial materials with the clinical development plan.  This is usually because the people and organizations responsible for each area don’t interact well and there is a lack of overall project management.  Most often, the focus of the company is the clinical […]
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New MAPP for FDA Accepting Alternate Compendia for CMC standards

On 11/3/2007 FDA issued a new MAPP* entitled “Acceptability of Standards from Alternative Compendia (BP/EP/JP)”.  Although directed at new drugs, one can probably argue that the policy should also apply to the Office of Generic Drugs.  Up to now, reviewers seemed arbitrarily accepting or denying the use of BP, EP and JP grade excipients and […]
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505(b)(2) – Part 2: The Assessment: Safety Review

Of course my product is safe! – the RLD was shown to be safe. Perhaps so.  The FDA approves products based on a risk/benefit; is the risk of taking the drug outweighed by the benefit?  Would FDA approve the RLD using today’s standards?  What changes from the RLD are we proposing to make in this development […]
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