Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

	Here in sunny Arizona, PDA is holding its annual conference, a chance to present data and discuss all aspects of sterile manufacturing. The theme for the first day of sessions was personalized medicine, an area where cell-based therapies, vaccines, and antibody therapies hold much promise. The day began with a keynote address by David Shanahan, president of the Mary Crowley Research Center. Shanahan discussed a vision of cancer treatment as highly personalized, where each patient’s cancer would be analyzed at the genetic level and matched to a combination therapy that specifically targets the markers expressed by the tumor. Antibody therapy would then be followed by an antigen-matched vaccine. Shanahan envisages a day when every hospital pharmacy will be stocked with a hundred or more highly specific therapies, with good enough side effect profiles that they can be delivered in combination or in rapid succession. While this is still a vision of the future, Shanahan believes that it’s one that can be realized: genomic tools have become fast and portable, mAb therapies are proliferating, and small, flexible manufacturing facilities exist that can produce multiple products in small quantities.

	Shanahan’s presentation was followed by a breakout session on manufacturing of personalized medicine. The speakers, Greg Whitehead, director of corporate quality assurance at Dendreon, and John Butler, Global Project Leader at Bayer Innovation, discussed the manufacture of autologous therapies. Autologous therapies, which are therapies derived from one patient and designed for one patient, present special manufacturing challenges. Whitehead explained in his talk that autologous therapies had to be manufactured meeting all the requirements of GMP, but with additional control to ensure integrity from the moment the cells are collected from the patient to the moment they are infused back in. In addition, Dendreon’s therapy is manufactured in and delivered to the patient in a short timeframe that doesn’t accommodate long-term sterility assurance. To accommodate this, he explains, Dendreon pays careful attention to traditional sterility controls, and uses orthogonal methods such as gram staining and rapid microbial testing. The short turn-around time also makes batch review and deviation resolution difficult, problems that are countered with efficient scheduling and robust contingency plans.
	Butler discussed the manufacture of an autologous vaccine product, created by raising antibodies against a patient’s tumor. This particular product is highly variable from patient to patient, which means from batch to batch. Butler discussed strategies for reducing cost that included implementing automation early on, avoiding redundancy of assays, and reducing QA/QC sample requirements. Because the volume of product they make is so low to begin with, QA/QC sample requirements can be a significant proportion of the volume produced. As an example, Butler said that of 100 vials produced in a lot, only 20 of those were destined for the patient, and the rest used for QA/QC. Butler concluded his talk by stressing the importance of working closely with regulators to address manufacturing issues that are unique to this class of product.

Articles

Here in sunny Arizona, PDA is holding its annual conference, a chance to present data and discuss all aspects of sterile manufacturing. The theme for the first day of sessions was personalized medicine.

PDA Meeting Highlights the Challenges of Personalized Medicine

 describing cGMP for preparing media fills for validation of aseptic preparations for positron emission tomography (PET) drugs. Most PET drugs, which are used for imaging, are given parenterally, and produced by aseptic processing. PET drugs came under the auspices of FDA relatively recently, with the passage of the 1997 Food and Drug Administration Modernization Act, and minimum cGMP standards for this class of drugs were established in 2009. A guidance for preparing new drug applications and abbreviated new drug applications for PET drugs was issued in March 2011, and in comments to the March 2011 guidance and in questions raised at the public meeting, stakeholders requested that FDA provide guidance on media fills for validation of aseptic preparation for PET drugs. This most recent guidance is designed to help manufacturers of PET drugs comply with FDA regulations. 

A media fill is a simulation of the aseptic process in which vials are filled with microbial growth medium instead of drug product to test whether the aseptic procedures are adequate to prevent contamination during actual drug production. The guidance document outlines the design of a media fill simulation, describes an example of an appropriate growth medium that can be used, and recommends how often a media fill should be done. In addition, the document provides guidance for qualifying growth media, including the performance of growth promotion tests to test whether the medium is capable of supporting microbial growth. Finally, the guidance describes positive controls for the media fill simulation.

FDA has released a final guidance describing cGMP for preparing media fills for validation of aseptic preparations for positron emission tomography drugs.

FDA Issues Final Guidance for Media Fills for Validation of Aseptic Preparations for PET Drugs

 that beginning in March 2012, the first shipments of atorvastatin, the generic version of Pfizer’s Lipitor, had been sent to US markets from its new Mohali manufacturing facility located in Punjab, India.

 from FDA in November 2011, to produce atorvastatin at its Ohm Laboratory site in the US, but its Paonta Sahib, Batamandi, and Dewas, India facilities have been on FDA import alert since 2008. According to the company’s press release, Ranbaxy’s Mohali facility was granted approval from FDA in October 2011 to manufacture and market atorvastatin 10-, 20-, 40-, and 80-mg tablets. Ranbaxy expects the Mohali facility to manufacture oral solid products for export to US, EU, and other countries based on filings and after receiving the necessary approvals.

Arun Sawhney, CEO and managing director of Ranbaxy, said in the release, “The resumption of supplies from India into the US market, is a significant milestone for Ranbaxy. This is a testimony to our commitment to provide quality affordable medicines to the US healthcare system. Going forward, our Mohali facility will cater to the US and other geographies, improving access to medicines, in these regions.”

Ranbaxy Laboratories announced that beginning in March 2012, the first shipments of atorvastatin, the generic version of Pfizer's Lipitor, had been sent to US markets from its new Mohali manufacturing facility located in Punjab, India.

Ranbaxy Begins Shipping Generic Lipitor From Indian Facility

	With around 80% of APIs manufactured outside the US, many in developing nations without strong regulatory oversight, ensuring the quality and safety of the US’s drug supply is a herculean task. FDA has already taken steps to increase the number of overseas inspections, but it is impractical to assume that one agency is capable of inspecting the world’s manufacturing operations on its own. The Institute of Medicine released a 

 on Apr. 4, 2012 outlining several practical steps that FDA could take to strengthen supply-chain security.

	One recommendation that stands out is that regulatory bodies in developed nations should work together to plan inspections and pool data, and should develop a harmonized set of inspection requirements so that inspections made by one country do not have to be repeated by other countries. According to the accompanying 

, “The report urges FDA and its technologically advanced counterparts in the European Union, Canada, Japan, Norway, Iceland, Switzerland, Australia, and New Zealand to plan a system for mutual recognition of one another’s inspections, which would eliminate the wasteful duplication of effort. There is no need for American and European inspectors to examine the same facilities, especially when a vast number of facilities go uninspected.”

	FDA has already begun the process of data sharing with regulatory bodies in Europe, the UK and Australia. A pilot program ran between 2009 and 2011 that resulted in the exchange of nearly 100 inspection reports and in nine collaborative inspections, according to an FDA 

 its Pathway to Global Product Safety and Quality,  a roadmap to continue the collaborative approach to assuring the safety of globally-sourced products. However, FDA’s blueprint falls well short of the recommendation of shared inspections put forth by the Institute of Medicine.

	It’s clear that no one country can inspect every plant in the world. But by pooling their resources, countries with similar regulatory requirements could accomplish a lot more than any one could accomplish alone.

With around 80% of APIs manufactured outside the US, many in developing nations without strong regulatory oversight.

Pooling Resources to Strengthen Supply-Chain Security

 to Steven Victor, CEO of IntelliCell Biosciences for a violation of the Food, Drug, and Cosmetic Act (FD&C Act), and for violations of cGMP and Good Tissue Practice (GTP) in the manufacture of its adipose tissue-derived stem-cell product.

IntelliCell’s product is derived from aspirated adipose tissue that is processed to produce a fraction containing adipose-derived stem cells. The cellular product is then readministered to the donor patient as an autologous therapy. Uses that the company promotes for the product include treatment of wrinkles and osteoarthritis, and for breast augmentation.

Human cells, tissues, or cellular and tissue-based products are not considered to be biological drug products provided they meet the criteria listed in 21 

 1271.10. Those requirements stipulate that the product be minimally manipulated and intended only for homologous use.

However, according to the FDA Warning Letter, Intellicell’s cellular product did not meet all of the criteria in 21 CFR 1271.10 because processing altered the relevant characteristics of the adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement. FDA also found that the treatments for which the cellular product was recommended did not meet the requirements for homologous use. FDA, therefore, found the product to be a drug under 201(g) the FD&C Act and a biological product as defined in section 351(i) of the Public Health Service Act [42 U.S.C. 262(i)]. Because the product lacked either an investigational new drug application or a biological license application, FDA found it to be in violation of the FD&C Act.

The Warning Letter also listed 16 violations of cGMP and GTP that were identified after a November 2011 inspection. The violations included deficiencies in sterility control and assurance, insufficient product characterization and quality control, lack of written records for equipment cleaning and maintenance, and inadequate labeling. The company had requested extensions for replying to the inspection report on Jan. 30, 2012, and Mar. 9, 2012. The Warning Letter indicated that the minimal responses received so far were inadequate and requested a response within 15 days to inform the agency of any additional steps that have been taken or will be taken to correct the noted violations and to prevent their recurrence, along with documentation necessary to show that correction has been achieved.

On Mar. 13, 2012, FDA issued a Warning Letter to Steven Victor, CEO of IntelliCell Biosciences for a violation of the Food, Drug, and Cosmetic Act, and for violations of cGMP and Good Tissue Practice in the manufacture of its adipose tissue-derived stem-cell product.

FDA Issues Warning Letter to IntelliCell Biosciences

	Personalized medicine is gaining traction as scientists gain greater understanding of disease processes. Such an approach depends on the correct and reliable identification of an underlying biomarker, whether the biomarker is a genetic marker, receptor expressed by a tumor cell, or metabolite indicating some underlying condition, that can predict whether a patient is likely to respond to a particular therapy. Genomics and proteomics are methodologies involving large datasets of genetic or protein markers that are analyzed to produce an individual profile. Such methodologies are potentially quite powerful, but quite complex.

	A recent high-profile cancer study conducted at Duke University relied on genomic analysis of tumors to tailor treatment to individual patients. Questions about the validity of the tests were raised at the outset of the trials by outside researchers, but the trials went forward anyway. In July 2010, more than 30 outside scientists asked the National Cancer Institute (NCI) to intervene and suspend the trials until the gene-expression tests could be reviewed adequately.

	Wishing to avoid this type of expensive and potentially harmful error in the future, NCI and FDA requested that a study be performed by the Institute of Medicine (IOM) to recommend responsibilities and best practices for the investigators, research institutions, funders, regulators, and journals involved in development and dissemination of clinical omics-based technologies. The 

 was released on Mar 23, 2012, and identifies best practices to enhance development, evaluation, and translation of omics-based tests. The report also offers guidance for ensuring that these tests are appropriately assessed for scientific validity before they are used to guide patient treatment in clinical trials.

, chairman of the IOM committee Gilbert Omenn, professor of internal medicine, human genetics, and public health, and director, Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor says, “We hope that this report will help all members of the investigative team understand the entire pathway of translating omics discoveries into clinical tests and recognize and avoid the potential pitfalls at each stage. We believe that past problems, such as the Duke case, could have been prevented had a clearly defined process been available and been utilized. Scientific and clinical progress in omics test development will be accelerated if these recommendations are broadly adopted.”

	Anyone who has ever taken a computer programming class is probably familiar with the phrase, “Garbage in, garbage out.” This axiom is just as easily applied to the field of personalized medicine. For personalized medicine to work, drug developers and clinicians need to pay as much attention to the validity of the biomarker test as to the efficacy of the treatment.

Personalized medicine is gaining traction as scientists gain greater understanding of disease processes.