Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

 regarding the issuance of warning letters to the pharmaceutical industry. Published in the 

 on 11 August, the programme is meant to better support public health protection by establishing a timeframe for “the submission and agency review of post-inspection responses to inspectional observations” that are sent to a company 

FDA 483 forms are issued to companies after an inspection to highlight “objectionable conditions” relating to the manufacturing process or products, according to the announcement. Companies are asked to respond to the FDA if they have an objection to an observation or if they have a corrective action plan for the observations noted. Warning letters, on the other hand, are issued when the agency, after a thorough review, finds a significant violation of the Federal Food, Drug, and Cosmetic Act during an inspection. 

Because a company’s response  or in most cases, multiple responses  to an FDA 483 form can delay the issuance of a warning letter, the agency is now planning to issue a warning letter  when appropriate  if the company fails to respond to a 483 within 15 business days. If a response to a 483 is received within 15 business days, the FDA will conduct a review of the response “before determining whether to issue a warning letter.” 

If a warning letter is still issued after receiving a firm’s timely response to 483 observations, the warning letter will recognize that response. If 483 observation responses are received after the 15-day period, and the agency issues a warning letter, the FDA will consider those responses to be direct responses to the warning letter rather than to the 483. 

The FDA reiterates in the announcement that the agency can issue a warning letter at any time, independent of receiving a 483 response. 

The programme, which correlates directly with FDA Commissioner Hamburg’s 

announcement on 6 August of a six-step improved enforcement plan

, will take effect on 15 September 2009. The programme will be evaluated after an 18-month period.

Articles

The FDA has announced a new programme regarding the issuance of warning letters to the pharmaceutical industry.

Warning letter enforcement begins in September

The US Food and Drug Administration announced a new 

  regarding the issuance of warning letters to the pharmaceutical industry. Published in the Aug. 11 

, the program is meant to better support public health protection by establishing a timeframe for “the submission and agency review of post-inspection responses to inspectional observations” that are sent to a company 

FDA 483 forms are issued to companies after an inspection to highlight “objectionable conditions” relating to the manufacturing process or products, according to the announcement. Companies are asked to respond to FDA if they have an objection to an observation or if they have a corrective action plan for the observations noted. Warning letters, on the other hand, are issued when the agency, after a thorough review, finds a significant violation of the Federal Food, Drug, and Cosmetic Act during an inspection.

Because a company’s response-or in most cases, multiple responses-to an FDA 483 form can delay the issuance of a warning letter, the agency is now planning to issue a warning letter-when appropriate-if the company fails to respond to a 483 within 15 business days. If a response to a 483 is received within 15 business days, FDA will conduct a review of the response “before determining whether to issue a warning letter.”

If a warning letter is still issued after receiving a firm’s timely response to 483 observations, the warning letter will recognize that response. If 483 observation responses are received after the 15-day period, and the agency issues a warning letter, FDA will consider those responses to be direct responses to the warning letter rather than to the 483.

FDA reiterates in the announcement that the agency can issue a warning letter at any time, independent of receiving a 483 response. 

The program, which correlates directly with FDA Commissioner Hamburg’s annoncement on August 6, of a six-step improved enforcement plan (see related story, 

FDA Commissioner Outlines Six-Step Plan for Improved Enforcement

.), takes effect Sept. 15, 2009. The program will be evaluated after an 18-month period.

The US Food and Drug Administration announced a new program regarding the issuance of warning letters to the pharmaceutical industry.

Warning Letter Enforcement Begins in September

 Supply-chain integrity is a critical concern for the pharmaceutical industry and its suppliers, and the industry is taking a step forward by addressing these concerns as a collective whole through the formation of Rx-360. Launched in June, Rx-360 is a nonprofit international pharmaceutical supply-chain consortium whose mission is to create and monitor a global quality system by adopting standards and best practices for the supply chain, supporting technology developments for supply-chain security, monitoring the supply chain, and developing shared audit programs. 


 Nearly 130 industry representatives attended the launch meeting in June to provide feedback on the consortium’s objectives and structure. Rx-360 is a voluntary organization. Membership in Rx-360 is open to suppliers of raw materials, components, excipients, and active pharmaceutical ingredients, and pharmaceutical and biotechnology companies. There are already about 10 members. Another 50 or so pharmaceutical and biopharmaceutical companies as well as 13 trade and standard-setting organizations such as the European Fine Chemicals Group, the Generic Pharmaceutical Association, the International Pharmaceutical Excipient Council of the Americas, the National Institute for Pharmaceutical Technology and Education, the Parenteral Drug Association, and the Society of Chemical Manufacturers and Affiliates, have expressed interest in joining. 


There will be a membership fee, which has not yet been set, but proposals range from $2000 to $20,000, depending on the number of consortium members. Whether fees will be tiered for large and small companies was also still under discussion at press time.



 The consortium’s founding panel members have not publicly disclosed their names or their company affiliations, but Martin Van Trieste, vice-president of quality at Amgen (Thousand Oaks, CA) is functioning as the consortium’s interim director. Van Trieste addressed the core reason for forming Rx-360 at the launch meeting. “Because the economic gain for adulterators is great, the pharmaceutical supply chain is at risk. A crisis like the heparin incident will happen again; it’s just a matter of when,” he said. “We can’t ask regulators to police our suppliers-it’s our legal responsibility.” 


 Industry seems to agree. In a live poll conducted at the meeting, 100% of voting attendees said they believe a consortium like Rx-360 is a necessity in the current environment. Rx-360 plans to address its goals during a three-year period as follows: 
•    Year 1-Adopt standards and best practices: Rather than add to the extensive list of existing regulations, the consortium intends to act as an “umbrella” by adopting already existing standards which it feels will improve supply-chain performance. Members may consider writing new standards in the future if any gaps in standards are identified.
•    Year 2-Implement a shared supplier-audit program: Rx-360 intends to provide to the industry with a wide range of auditing services, including a system that will allow companies to share audit findings and corrective actions. 
•    Year 3-Develop technology: Rx-360 plans to work with academic institutions and research organizations to develop related supply-chain security technologies such as tools that can detect contaminated or adulterated materials.
•    Year 3-Monitoring: The consortium sees itself as a future “clearinghouse for suspicious supplier and supply-chain information that might impact patient safety,” according to the consortium. This clearinghouse, for example, may involve electronic communications to alert consortium members to potential supply-chain disruptions. 


 The primary push for Rx-360 is the idea of sharing supplier-audit reports. Nearly 80% of participants voting at the launch meeting said their current audit programs need work. And according to Van Trieste, the head of the European QP Organization stated that industry would have to conduct 800,000 supplier audits per year to meet current and future regulatory expectations. Yet, “if just 100 companies would use 50 shared audits, industry could save $50–$80 million a year,” said Van Trieste. More important than the cost savings is that, through shared audits, more information can be obtained about a supplier because all parties involved are willing to spend more time on the audit-and more information allows firms to make better decisions, he added. A shared program would also benefit suppliers because they would be able to consolidate multiple customer audits through a single shared audit. 


 Rx-360 is proposing three types of shared supplier audits. The “sponsored” model involves a consortium member company paying for Rx-360 auditors to conduct an audit of a supplier of their choice. This model is essentially a third-party audit system, which benefits smaller pharmaceutical and biopharmaceutical companies that do not have their own audit staff as well as larger companies that want to audit a supplier in a region where they do not have audit coverage. Once completed, the audit report would go into the consortium’s shared audit database so that other members could purchase it. Sixty-seven percent of voting participants at the launch meeting said they support this model. 


 The “Rx-360” model would involve a joint decision among a certain number of consortium members to audit a supplier. Once an Rx-360 team completes the audit, the members that requested the audit would receive the audit report. In addition, the report would go into the shared audit database for purchase by other members. The Rx-360 model was the group favorite at the launch meeting, with 90% of voters supporting the idea as a viable approach.


 The “subscription” model would allow consortium members to submit and pull from a shared database audit reports that have already been conducted, either by their own company or by a third-party. Eighty-one percent of launch-meeting voters support this model. 


 Although there is great support for Rx-360’s proposals, there is a lot of work to be done before a shared audit program can be finalized. During breakout sessions at the launch meeting, industry representatives discussed some concerns about sharing audit reports. For example, what would be the qualifications of the Rx-360 auditors? Would there be an agreed-upon template for audit questionnaires? Given that different companies manufacture different types of drugs, would an Rx-360 audit or another company’s audit fulfill a different member-company’s audit needs?  

Reflecting these concerns, 16% of the voting participants at the launch meeting said shared audits were not an option, and another 33% said shared audits would require significant rework. That said, the remaining participants seemed very open to working with the current proposed program and its models. One potential solution discussed during the breakout sessions was that consortium members use an Rx-360 audit report as an initial assessment for their company to determine to what extent additional review or time is needed for their own audit of a particular supplier. 

During the next few moths, the Rx-360 advisory panel and consortium members have their work cut out for them. Priorities, according to Van Trieste, will be to grow membership; review and address feedback received from the Washington, DC, launch meeting; form various committees to build the consortium’s infrastructure (i.e., adopting audit standards and selecting a secure database to use); and arranging for a European launch meeting. 

To listen to a podcast interview with Martin Van Trieste, log onto 

 http://reg.accelacomm.com/servlet/Frs.frs?Context=LOGENTRY&Source=source&Source_BC=93&Script=/LP/50541861/reg&

A new industry consortium of pharmaceutical manufacturers and their suppliers addresses supply-chain integrity, including possible approaches to shared supplier audits.

Pharma Industry Consortium Rx-360 Tackles Supply-Chain Security

The US Food and Drug Administration announced its prescription drug user fee rates for fiscal year (FY) 2010 in the August 3 

. Each year, one-third of fees generated from the Prescription Drug User Fee Amendments of 2007 (PDUFA IV) come from fees for applications, establishments, and products, according to the announcement.

  The FY 2010 fees for applications requiring clinical data will be set at $1,405,500; applications that do not require clinical data or supplemental clinical data will be $702,750. FDA estimates that 25% of applications submitted each year arrive at the agency during the last three months of the year.

  Establishment fees for FY 2010 will be set at $457,200. FDA estimates that 450 establishments have been billed for FY 2009 fees and that, of those 450, 20 waivers or exceptions will be made before the end of FY 2009, on Sept. 30. In addition, another 15 exemptions will be made for orphan drug fees.

  Product fees for FY 2010 will be set at $77,720. FDA estimates that in FY2009, 2450 products will have been billed for fees. Of those, the agency expects to grant about 50 waivers and reductions by Sept. 30, 2009. Another 20 product fees will be exempted before the end of FY 2009 for orphan drug qualifications.

  Below is a comparison of the year over year fee increases:

  The total fee revenue amount for FY 2010 is $569,207,000. All fees are effective Oct 1, 2009.

The US Food and Drug Administration announced its prescription drug user fee rates for fiscal year 2010 in the August 3 Federal Register.

FY 2010 User Fees Released

Supply-chain integrity is a critical concern for the pharmaceutical industry and its suppliers, and the industry is taking a step forward by addressing these concerns as a collective whole through the formation of Rx-360. Launched in June, Rx-360 is a nonprofit international pharmaceutical supply-chain consortium whose mission is to create and monitor a global quality system by adopting standards and best practices for the supply chain, supporting technology developments for supply-chain security, monitoring the supply chain, and developing shared audit programs. 

Nearly 130 industry representatives attended the launch meeting in June to provide feedback on the consortium's objectives and structure. A voluntary organization, membership in Rx-360 is open to suppliers of raw materials, components, excipients, and active pharmaceutical ingredients, and pharmaceutical and biotechnology companies. There are already about 10 members and another 50 or so pharmaceutical and biopharmaceutical companies as well as 13 trade and standard-setting organizations such as the European Fine Chemicals Group, the Generic Pharmaceutical Association, the International Pharmaceutical Excipient Council of the Americas, the National Institute for Pharmaceutical Technology and Education, the Parenteral Drug Association, and the Society of Chemical Manufacturers and Affiliates, had expressed interest in joining.  

There will be membership fee, which has not yet been set, but proposals range from $2000 to $20,000 depending on the number of consortium members. Whether fees will be tiered for large and small companies was also still under discussion at press time. 

The consortium's founding panel members have not publicly disclosed their names or their company affiliations, but Martin Van Trieste, vice-president of quality at Amgen (Thousand Oaks, CA) is functioning as the consortium's interim director. Van Trieste addressed the core reason for forming Rx-360 at the launch meeting. "Because the economic gain for adulterators is great, the pharmaceutical supply chain is at risk. A crisis like the heparin incident will happen again; it's just a matter of when," he said.  "We can't ask regulators to police our suppliers—it's our legal responsibility."  

Industry seems to agree. In a live poll conducted at the meeting, 100% of voting attendees said they believe a consortium like Rx-360 is a necessity in the current environment. Rx-360 plans to address its goals during a three-year period as follows:   

Year 1—Adopt standards and best practices: Rather than add to the extensive list of existing regulations, the consortium intends to act as an "umbrella" by adopting already existing standards which it feels will improve supply-chain performance. Members may consider writing new standards in the future if any gaps in standards are identified.

Year 2—Implement shared supplier audit program: Rx-360 intends to provide to the industry with a wide range of auditing services, including a system that will allow companies to share audit findings and corrective actions. 

Year 3—Develop technology: Rx-360 plans to work with academic institutions and research organizations to develop related supply-chain security technologies, such as tools that can detect contaminated or adulterated materials.

Year 3—Monitoring: The consortium sees itself as a future "clearinghouse for suspicious supplier and supply-chain information that might impact patient safety," according to the consortium. This clearinghouse, for example, may involve electronic communications to alert consortium members to potential supply-chain disruptions.

The primary push for Rx-360 is the idea of sharing supplier audit reports. Nearly 80% of participants voting at the launch meeting said their current audit programs need work. And according to Van Trieste, the head of the European QP Organization stated that industry would have to conduct 800,000 supplier audits per year to meet current and future regulatory expectations. Yet, "if just 100 companies would use 50 shared audits, industry could save $50–$80 million a year," said Van Trieste. More important than the cost savings is that, through shared audits, more information can be obtained about a supplier because all parties involved are willing to spend more time on the audit—and more information allows firms to make better decisions, he added. A shared program would also benefit suppliers because they would be able to consolidate multiple customer audits through a single shared audit. 

Rx-360 is proposing three types of shared supplier audits. The "sponsored" model involves a consortium member company paying for Rx-360 auditors to conduct an audit of a supplier of their choice. This model is essentially a third-party audit system, which benefits smaller pharmaceutical and biopharmaceutical companies that do not have their own audit staff as well as larger companies who want to audit a supplier in a region where they do not have audit coverage. Once completed, the audit report would go into the consortium's shared audit database so that other members could purchase it. Sixty-seven percent of voting participants at the launch meeting said they support this model.  

The "Rx-360" model would involve a joint decision among a certain number of consortium members to audit a supplier. Once an Rx-360 team completes the audit, the members that requested the audit would receive the audit report. In addition, the report would go into the shared audit database for purchase by other members. The Rx-360 model was the group favorite at the launch meeting, with 90% of voters supporting the idea as a viable approach. 

The "subscription" model would allow consortium members to submit and pull from a shared database audit reports that have already been conducted, either by their own company or by a third-party. Eighty-one percent of launch meeting voters support this model. 

Although there is great support for Rx-360's proposals, there is a lot of work to be done before a shared audit program can be finalized. During breakout sessions at the launch meeting, industry representatives discussed some concerns about sharing audit reports. For example, what would be the qualifications of the Rx-360 auditors? Would there be an agreed-upon template for audit questionnaires? Given that different companies manufacture different types of drugs, would an Rx-360 audit or another company's audit fulfill a different member company's audit needs?   

During the next few moths, the Rx-360 advisory panel and consortium members have their work cut out for them. Priorities, according to Van Trieste, will be to grow membership; review and address feedback received from the Washington, DC, launch meeting; form various committees to build the consortium's infrastructure (i.e., adopting audit standards and selecting a secure database to use); and arranging for a European launch meeting.  

To listen to a podcast interview with Martin Van Trieste, log onto the 

Industry is taking a step forward by addressing supply-chain integrity through the formation of Rx-360. PhamTech's podcast explores the subject.

Similar to the United States, authorities across the Atlantic also have changed the way pediatric formulations are regulated. In January 2007, the European Medicines Agency (EMEA) implemented a new "Pediatric Regulation" that requires pharmaceutical companies to submit a development plan known as the "pediatric investigation plan (PIP)" (this is essentially a drug-development plan) with their marketing authorization applications (known as new drug applications in the US) (1). As of July 2008, all new products in the European Union that have not been authorized in the European Union before Jan. 26, 2007, must contain the results of studies conducted based on a PIP unless a waiver or deferral has been granted (2). 

 According to EMEA, the new regulation "aims to facilitate the development and accessibility of medicinal products for use in the pediatric population, to ensure that medicinal products used to treat the pediatric population are subject to research of high quality, and are appropriately authorized for use in the pediatric population, and to improve the information available on the use of medicinal products in the various pediatric populations" (3). 

Meant to ensure necessary data are obtained for children aged 0 to 17 years without subjecting them to unnecessary trials or delaying the authorization of drugs for adult use, the plan can be modified as information is gained (3). The PIP must include the drug's formulation and study descriptions and must cover children from infancy to adolescence. If children are not targeted to use a particular drug, a PIP is not required (e.g., Parkinson's disease does not tend to affect children, so drugs targeted to treat Parkinson's would not need a pediatric formulation) (4). In this case, however, the company must obtain a waiver from EMEA allowing it to forego a PIP. Also exempt from the Pediatric Regulation are generic drugs, hybrid medicinal products, biosimilars, and medicinal products that contain one or more active substances of well-established medicinal use (1). 

Several incentives are included in the Pediatric Regulation. For example, manufacturers of older, off-patent drugs developed specifically for pediatric use can apply for a new pediatric use marketing authorization (PUMA) and, upon approval, obtain 10 years of data protection; orphan drugs receive 12 years (2). In addition, new drugs approved under the PIP receive a six-month patent extension. EMEA provides free scientific advice on pediatric development questions as well (5). 

Another important component of the regulation regarding postmarketing authorization is that once a medical product is authorized for a pediatric indication, the holder of the marketing authorization must, within two years of the date of authorization, place the product on the market. EMEA will make the deadline public to encourage compliance (3). In addition, if the manufacturer wishes to discontinue marketing its product after the authorization period has expired, then it must transfer the product data to a third-party (3). 

 In September 2008, the European Commission published the final version of a guideline on the "Format and Content of Applications for Agreement or Modification of a PIP and Requests for Waivers or Deferrals and Concerning the Operation of the Compliance Check and on Criteria for Assessing Significant Studies" (5). The guideline is meant to clarify what should be included in PIP documents and to define the criteria for pediatric studies started before and completed after the entry into force of the Pediatric Regulation (5). 

To further help industry comply with the new requirements, EMEA issued in November 2008 a concept paper on the "Development of a Quality Guideline on Pharmaceutical Development of Medicines for Pediatric Use" (6). The consultation period for this paper ended in November 2008 and at press time, a draft guideline based on the comments had not yet been issued. Once completed, the new guideline is expected to establish clear harmonized recommendations on all aspects to be considered in the development of a specific product (e.g., dosage form, excipient sensitivity) for the use in, or a subset of the, pediatric population, according to the concept paper (6). The guideline is also meant to help facilitate procedures for PIPs and for marketing authorization applications and variations (6). 

On Jan. 26, 2009, another portion of the Pediatric Regulation went into effect. For all new drug indications (e.g., a new route of administration or a new dosage form) of an already authorized, patented drug, a PIP or deferral/waiver is required with a company's marketing authorization application (2). In addition, as of June 12, 2009, EMEA will only accept electronic applications for PIPs, waivers, modifications, and compliance checks. 

Pediatric Formulations: Technical and Regulatory Considerations

Waivers and Deferrals Under the Pediatric Research Equity Act

1. EMEA, "Frequently Asked Questions on Regulatory Aspects of Regulation (EC) No 1901/2006 (Paediatric Regulation) Amended by Regulation (EC) No 1902/2006," (London, Sept. 2, 2008), 

www.emea.europa.eu/pdfs/human/paediatrics/52008506en.pdf

2. EMEA, "Better Medicines for Children: Overview of the European Medicines Agency's Role in the European Regulatory Environment for Paediatric Medicines," 2009. 

3. Official Journal of the European Union, "Regulation (EC) 1901/2006 Of the European Parliament and of the Council on Medicinal Products for Paediatric Use and Amending Regulation (EC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC, and Regulation (EC) No 726/2005, Dec. 12. 2006, 

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ: L:2006:378:0001:0019:EN:PDF

4. EMEA, "Paediatric Investigation Plans (PIPs), Waivers, and Modifications" (Brussels, Feb. 27, 2009), 

www.emea.europea.eu/htms/human/paediatrics/pips.htm

5. EMEA, Guideline on the Format and Content of Applications for Agreement or Modification of a PIP and Requests for Waivers or Deferrals and Concerning the Operation of the Compliance Check and on Criteria for Assessing Significant Studies (2008/C 243/01), (Brussels, Sept. 24, 2008), 

www.emea.europa.eu/pdfs/human/paediatrics/Guideline_2008_C243_01.pdf

6. EMEA Committee for Medicinal Products for Human Use, Paediatric Committee, and Committee on Herbal Medicinal Products, "Concept Paper on the Development of a Quality Guideline on Pharmaceutical Development of Medicines for Pediatric Use," (London, July 29, 2008), 

www.emea.europa.eu/pdfs/human/qwp/13893108en.pdf

A summary of recent changes to European regulatory requirements for pediatric formulations.