Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

	Through its continued effort to harmonize and update pharmaceutical standards, the 

 (USP) is revising and modernizing its chapters on elemental and organic impurities in pharmaceutical development and manufacturing.  To gain some insight on these changes and how they may affect the industry, 

 spoke with Kahkashan Zaidi, principal scientific liaison, USP, and Antonio Hernandez-Cardoso, senior scientific liaison, USP, about these updated 

	To hear more about elemental impurities standards, attend USP’s upcoming presentation, “

,” to be held on Thursday, May 18, 2017 at 10:30 am to 12 pm, as part of the Drug Manufacturing track at 

 What prompted the updates to the elemental impurities chapters?

 No specific event triggered the revision of the 

 standards. USP engages in continuous evaluation and revision of all its standards in order to maintain scientific and public health relevance.

	In addition to coordinating efforts in this area with FDA and the industry, USP worked closely with the 

 (ICH) to ensure alignment of its standards for elemental impurities with the ICH Q3D 

 <232> and <233> that drug manufacturers should be aware of?

 There are some key considerations for manufacturers regarding compliance with General Chapters <232> and <233>. 

 chapter <232> requirements are for drug products. This chapter is aligned with ICH Q3D in all respects but one: total parenteral nutrition products. Those are within scope for Q3D, but out of the scope of General Chapter <232>.  

	One thing for manufacturers to keep in mind is that General Chapter <233> does not restrict them to use only the ICP technique (Inductive Coupled Plasma). This chapter is very flexible and offers guidance on validation requirements for several alternative procedures to test for elemental impurities.

 <232> and <233> harmonized with ICH requirements and FDA expectations?

 USP’s toxicology experts worked closely with the ICH Q3D toxicologists to achieve a consistent outcome. USP revised the content in General Chapter <232> after this collaboration to ensure alignment across both documents.  USP’s Elemental Impurities Expert Panel and Chemical Analysis Expert Committee added additional elements and corresponding limits in General Chapter <232> based on the collaboration with the ICH Q3D. 

 In addition to the chapters on elemental impurities, USP updated chapters on organic impurities. Why does USP feel it is necessary to modernize organic impurities testing?

 USP continuously reviews and modernizes its quality standards to incorporate new technologies, testing methods, and procedures, as well as to reflect the best practices in industry and to keep the standards in the 

	In 2013, USP’s Expert Panel on Modernization of Organic Impurities Testing in Drug Substances and Drug Products decided to revise 

 General Chapter <1086> to be in line with current regulatory thinking on over-the-counter (OTC) and generic products regarding organic impurities testing. Also, recommendations from a stakeholder survey indicated that the use of terminology and principles established in ICH Q3A and Q3B guidelines should be reflected in any effort to modernize chapters.

	The Expert Panel was also tasked with evaluating the advantages and disadvantages of moving relevant text from the current General Chapter <1086> to a new General Chapter below <1000>. General Chapters numbered above <1000> are informative while General Chapters below <1000> contain mandatory requirements.  

<1086> and what should drug manufacturers know about the upcoming <476> chapter?

 Based on the input received from the stakeholder survey and from a workshop co-sponsored with FDA on organic impurities in OTC products, the Expert Panel decided to update <1086> to reflect the terminology and principles of ICH Q3A and Q3B. The intention is to add some statements and applicable information to keep them aligned for existing and legacy products.

	Regarding <476>, the Expert Panel decided to create a companion mandatory chapter including acceptance criteria aligned with the organic impurities thresholds established in the ICH guidelines. The proposal (similar to the current approach in the 

) is to incorporate cross references in monographs to address unspecified and total impurities, on a case-by-case basis, based on maximum daily doses (MDD), as outlined in ICH Q3A and Q3B.

	The final piece of information to be synchronized will be the General Notices. Once the final text in <1086> and <476> is approved, the current text in General Notices will be revised accordingly.

 When will these changes to impurities testing and requirements be implemented?

 The work on revising these General Chapters is ongoing. The first step was to address the comments received when the chapters were open for public comments and to make the relevant changes.

	New versions of <476> and <1086> will be published in 

for another round of public comments. Some of the changes being considered are the inclusion of cross references in monographs, better coordination with the Expert Committee on OTCs to synchronize implementation activities, incorporating decisions taken with FDA on terms used (“Disregard Limits” 

 “Reporting Thresholds”, for example), and the possibility of a delayed implementation date for compliance.

 What will participants learn at your CPhI North America session?

 Participants will learn about the work being conducted at USP through Expert Committees and Expert Panels to modernize General Chapters <486> and <1086> (related to organic impurities). They will also learn of any updates to General Chapters <232> and <233> (elemental impurities), particularly as related to the upcoming official date for compliance (January 2018).

Articles

At CPhI North America 2017, the US Pharmacopeial Convention will be discussing its upcoming revision and modernization of the standards for elemental and organic impurities.

Modernizing Organic and Elemental Impurities Standards

Modernizing Organic and Elemental Impurities

 Which parts of FDA’s quality agreements guidance, which was published in November 2016, should manufacturers pay close attention to? Are there similar guidelines in Europe?

 Although the entire FDA guidance should be paid close attention to, one particular aspect of interest to manufacturers relates to ‘Approving or Rejecting Changes that Affect Product Quality and cGMP Compliance’ (Case 5 of the guidance). Change management can be challenging when a sponsor and contract acceptor disagree. When this occurs, the FDA’s guidance provides clarity around each party’s role and responsibilities which allows the two groups to better overcome these challenges. In Europe, written quality agreements/contracts are mandated within existing regulations, namely 

 Volume 4, Part I, Chapter 7 Outsourced Activities; Part II Paragraph 16 Contract Manufacturers (including Laboratories); and Part III Pharmaceutical Quality System (International Council for Harmonization Q10) Paragraph 2.7. Management of outsourced activities and purchased materials.

 How can quality agreements enhance the sponsor/contractor relationship?

 While many sponsors and contractors may share a close commercial relationship, quality agreements add a compliance component. This helps to build more of a common understanding of each side’s needs, building additional trust. Possessing a written framework that guides the relationship on both an operational and compliance basis allows for issues to be addressed at a level that is likely more amenable to cooperation and often eliminates legal team involvement.

 How do quality agreements enhance the overall quality of pharmaceutical products?

 Although the sponsor outsources certain activities, it maintains full responsibility for everything that the contract acceptor does when interfacing with regulatory authorities. Thus, the responsibility for manufacturing safe products of a high quality remains with the sponsor. Therefore, the sponsor has great interest in writing quality agreements that assure the maintenance of high quality and compliance levels by the contractor. 

 How should quality agreements be designed?

 Quality agreements should include clarity in terminology, unambiguously defined roles and responsibilities, and a precisely defined scope of the agreement. These documents are designed for project managers, operational staff, and quality experts. With these users in mind, the language of quality agreements should be appropriate for that audience and not be written like a legal document. Quality agreements should also be written as separate documents from commercial contracts to retain the flexibility to update and change these as needed.

 What are some of the mistakes pharma companies make when developing quality agreements?

 Issues are more likely to arise when both parties involved are not properly aligned, which may lead to a misunderstanding on expectations. Additionally, gaps may surface in specific areas where the sponsor and contractor have varying levels of expertise, such as information technology. To avoid potential gaps or conflicting details within an agreement, the contractor and sponsor should maintain a close relationship with clear objectives and a mutual understanding of the quality agreement.

	When referring to this article, please cite it as S. Haigney, "The Importance of Quality Agreements," 

Pharmaceutical Technology asked Siegfried Schmitt, principal consultant at PAREXEL, about the importance of quality agreements in the sponsor/contractor relationship.

The Importance of Quality Agreements

 spoke with Tommy Fanning, head of biopharmaceuticals for 

, to get a perspective on how Brexit may affect the pharmaceutical industry.

 How does Brexit specifically affect the biopharmaceutical industry?

 I think how it’s affecting it today is they’re all probably in a huddle trying to decide what footprint they need in Europe in the future. So, if you think about the biopharma industry, they will already have a strong footprint across Europe, but some of those mid-sized companies may only be in the United Kingdom in the European context. And they’re obviously going to have to look at what they need to do to be sure their products are licensed, approved, and sold in all markets in the same way they’ve always been done.

	If we look at the broader sense as well around Brexit and in the context of Britain itself, Britain has always prided itself in terms of its research and development ability around medicines. If you look at areas like Oxford or Cambridge, there are very strong clusters of discovery work going on and development work in small early-stage companies. Those companies themselves will be looking to the future and seeing where they need to do that.

	And the other piece in all of that, when Britain decides to invoke Brexit, what will happen to the funding that was coming from European funds for medicinal or scientific research and how will that be replaced? So, I think there are a lot of questions in there. If we talk about the idea of business decisions, it’s around the passporting of and approval of products for sale in Europe. If you think of innovation, it’s around research and research funding.

	And if we think about global expansion, and this is something we here in Ireland look at very closely, global expansion can take a number of forms,  particularly in relation to manufacturing. As it turns out, Ireland has a much stronger base in manufacturing across sectors if we go outside life sciences for a minute. Twenty percent of value added to GDP in Ireland is from manufacturing. That figure is a lot less in the UK today. And then when we look more specifically, and I’ve seen some figures recently from the 

 on this front, quite a number of foreign direct investment (FDI) projects that go into the UK [are often] for the UK market. Where as if you look at Ireland, Switzerland, or outside Europe at places like Singapore we’re looking at much larger investments, capital investments, and much larger plants serving global markets. So, as a first in the context of Brexit, yes there will be some things for the companies in the biopharmaceutical industry to look at. But on the same basis, I think companies just need to clean house in the context of products for Europe. 

 What is the possible long-term impact of Brexit on the pharma industry?

 I think the long-term impact on the pharma industry will be quite large. I would suspect, rather than know for a fact, that the companies will reduce the number of serious capital investments that they might make in the UK. I don’t know where those investments might go otherwise. There is another fly in the ointment in all of this, of course, which is in America, Donald Trump, and the current conversation there about bringing back manufacturing to the US. So, I could also see companies looking at having a stronger manufacturing base in the US and perhaps a smaller footprint very specifically for the European market. Because if we think about many of the plants today that are in Europe, they are not just manufacturing for Europe but they are also FDA approved, sending back API or sending back drug substance for the biologics side for final manufacture in the US. And that might change, but it’s too early to say.

 Will Brexit have a negative impact on the UK?

 In a broad sense, I think so. The British prime minister, Theresa May, and her team, has a working team around Brexit from the pharmaceutical industry, which includes GSK and AstraZeneca, the two major drug companies with strong footprints in the UK today. But I think there are too many things that will require global drug companies to look elsewhere. I don’t think overnight, there’s going to be a big reduction in employment, but I think over time, the commercial reality will require these companies to have another location. 

Are there specific countries that are well suited to the relocation of European Medicines Agency (EMA)?

 EMA, if Brexit is invoked, will move out of the UK. If there are other agencies, they will, likewise, move outside of the UK, because the UK will no longer be part of Europe. So, we just have to take that as a fact.

	In the context of  EMA, quite a number of European countries have put a hand up and said: we will be bidding for this; we have the right location for this. We likewise in Ireland feel we have a strong case to be made. We have a very strong industry here. We have a very strong regulator in the Health Products Regulatory Agency (HPRA), which is a mirror of what the Medicines and Healthcare products Regulatory Agency (MHRA) is in the UK.

	Our HPRA is already doing a lot of work with EMA; it is already doing training for EMA; and sitting on management committees within EMA. So, they understand the needs of EMA very well. But if you bring that out a bit and look again at Ireland as a location, I think the most important thing is to look at EMA itself and how important it is to Europe, how important it is to European citizens that it continues to work and operate in a professional manner.

	EMA is a very highly respected agency today with some very good people based in Canary Warf in London. Those people need to come with the agency. The work they do needs to continue with no hiatus. It has to be in some way seamless. And, we do think that Dublin can provide that venue. We’re building quite a lot of new high class A buildings, office buildings, in the city of Dublin, a number of which could be suitable to house EMA. We’ve got a multicultural, multilingual environment in Dublin today, and that’s just not in the life-sciences community, it’s also from the digital media community. All of the top 10 born on the web companies have bases in Ireland with multilingual workforces: LinkedIn, Google, Facebook, Twitter, they’re all here and in large numbers.

	And EMA won’t just require scientifically qualified staff. EMA will also require IT staff, data analytic staff, administrative staff, and financial staff. We do feel that Dublin will be a very good location. Ryanair [offers] low-cost flights from Dublin to almost all locations in Europe today. Something we couldn’t have said a decade ago. And that continues to expand. So, I think Dublin is also very well connected in terms of the industry.

	Another little piece that maybe is not so clear right now is the fact that today EMA looks after and regulates the medicines products industry, but I would expect, and this is just something from my own experience, that they will also in the future, because of the advent of combination products, want to be looking at regulating devices as well. And besides Ireland having very strong global biopharma industry here, we also have a very strong medical technologies industry, so we have experience on both sides of that fence.

 Has any country done anything specific to throw their hat in to move EMA there? Has a process started yet?

 No. Any country that has put their hand up has done so in a vacuum, because there is no process today. There is no timeline today. So, it’s a question of saying, well look, we want to be ready when that time goes. So, in an Irish context, there is a working group across all stakeholders within government and then consultation with those outside of government to make sure that Ireland’s bid will be the best it possibly can be. The same would apply for any other country. The one exception in terms of has any country done anything, I believe Italy are offering a building, as in they had an expo in Milan a number of years ago and they have a building or set of structures that could be suitable, but that is the only specific proposition that I’ve seen put forward.

 Have you seen any action at pharmaceutical companies in response to Brexit (e.g., plans to move locations, changes in regulatory submissions, etc.)?

Well if you look at the importance of EMA again, it is an attractor in itself. And you will find there is quite a large number of European headquarters or large European footprints of all of the drug companies in London. Most specifically, the Japanese have come out with an open public letter to say please don’t move the EMA out of London because the majority of their European headquarters are there. I don’t believe that’s a possibility. So, on that basis, the question arises, will these companies then move their bases somewhere else? And this would include teams that would have the commercial responsibilities for Europe, the management of clinical trials for Europe, regulatory affairs, pharmacovigilance, pharmacoeconomics, those type of activities, and then backing those up, more recently, data platforms and data analytics specifically for the commercial or business development people. So, I think there’s quite a lot of questions to be asked and no answers right now.

	What we’re seeing in a broader sense, one of the big areas is obviously financial services and financial products being passportable in Europe. I think the same analogy holds true for drugs and the approval of those drugs. And on that basis, I think right now, the companies are looking at what they need to do to continue to do business in Europe. And that doesn’t mean in any way closing down operations they already have in the UK. What I can see, and some companies are doing this already, is the idea that they might have a satellite group. They might build up another team that complements what’s in London because there’s a talent pool and there’s a skill pool there already that the companies will not want to lose.

Pharmaceutical Technology spoke with Tommy Fanning, head of biopharmaceuticals for IDA Ireland, to get a perspective on how Brexit may affect the pharmaceutical industry.

A New Location for EMA?

Pharmaceutical companies are in the business of improving the public’s health and quality of life. Regulators and standard-setting organizations exist to both guide the pharma industry in their endeavors and to ensure public safety. It’s a partnership that can sometimes be contentious but is, ultimately, beneficial to all. 
	
	As the pharmaceutical market continues to expand globally, international regulators are making an effort to harmonize regulations and standards and to protect the complex supply chain. Pharma companies are also making an effort to stay compliant with worldwide guidelines in an ever-changing regulatory environment. 

	“There is a lot of effort on the part of drug companies to research and make sure they are compliant with the various worldwide manufacturing regulations. For the most part, GMP requirements are rather consistent worldwide,” says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates. “The differences that exist can be managed by applying the strictest requirement to the products that would ensure its acceptance across the globe. Issues may arise when a standard applied to the technology is changed and the new requirement is stricter than its predecessor. Companies need to fully understand their product in the development stage to be able to address the ever-changing regulations.”

	Regulators, government agencies, and standard-setting organizations can be the catalyst for the development of new and innovative therapies as a response to world health crises, and there are a variety of ways industry can get involved with these initiatives. “There are many trade organizations that offer workshops and conferences that address some of the unmet medical needs facing the global community. Companies should make sure they are on the mailing lists for these organizations so they can receive notice of upcoming conferences and choose the ones that seem most pertinent to their business. These conferences not only [provide] cutting-edge information, but they also offer an opportunity for people to network and discuss issues and potential solutions to them,” says Schniepp.

	Manufacturers must navigate the regulatory waters to ensure their products meet the proper requirements. In the following sections, industry experts give advice about getting involved with standards development, improving the product approval process, preparing for inspections, and responding to regulators. 

	
	Industry standards and monographs, such as the 

), can help pharmaceutical manufacturers get their products approved by regulatory bodies and into patients’ hands. According to a US Pharmacopeial Convention (USP) spokesperson, “USP’s public standards can help facilitate the application process by establishing standards that sponsors reference in applications and licenses to demonstrate the quality, purity, and strength of their drug products.”

	And international standard-setting organizations emphasize the importance of industry input. USP encourages pharma companies to participate in the development of public standards. Susanne Keitel, director of the European Directorate for the Quality of Medicines and Healthcare (EDQM), which is in charge of the Ph. Eur., would like to see industry become more active in the development of pharmacopeial standards, such as nominating experts to participate in developing standards. Keitel states, “The knowledge and experience of experts from pharma companies is crucial to ensure robust, state-of-the art, validated, and affordable test methods and monographs … and relevant standards worldwide. No pharmacopeia could do without the contributions of and collaboration with industry.”

	USP’s Global Health Monographs program addresses treatments for major health concerns, such as malaria, or unmet needs in underserved communities outside of the United States. Pharmaceutical companies can help by donating specifications and materials.  Working with USP on pending monographs is another way industry can get involved. “These are monographs or monograph revisions for certain substances that have been submitted or are intended to be submitted to FDA for approval but have not yet received approval. By approaching USP early in the process, USP can more readily close the gap that otherwise might exist between FDA approval and the publication of an applicable USP monograph,” says a USP spokesperson.

	Researching and developing a pharmaceutical product for eventual manufacture and distribution is a long and expensive process, and regulations play a prominent role. By working closely with regulators, pharma companies can make the product-approval process smoother. “The approval process can be improved when sponsors work hand in hand with regulatory agencies during the approval process, answering reviewers’ questions as they arise, and providing timely information regarding manufacturing processes and quality control strategies,” says Russell Madsen, president of The Williamsburg Group. 

	“In my opinion, sponsors can be more open with FDA during the development process,” says Mukul  Agrawal, PhD, president MA Pharmaceutical Consulting and member of the Bioequivalence Focus Group steering committee at the American Association of Pharmaceutical Scientists (AAPS). “There are apprehensions about how FDA will perceive that and what if FDA asks for something unreasonable? To the contrary, FDA is helpful and appreciates the efforts of sponsors in doing things right and according to FDA’s expectations. While there is a need for balance in these interactions, it is better to maintain open communication with FDA. It is also possible to have a dialog with the FDA about their expectations, and if data can be provided to support justification for doing something differently, it should be discussed and agreed to with them,” says Agrawal. 

	Not providing enough information about manufacturing and control strategies can complicate FDA’s evaluation of a drug product, according to Madsen. “Not providing information in the proper format (e.g., electronic common technical document [ECTD]) and providing insufficient or incomplete information …  not responding in a timely fashion to requests for additional information or answering questions posed by regulatory agencies [are mistakes companies make],” says Madsen.

	Knowing what’s expected by the regulatory agency is key. “The most frequent mistake in my opinion is that the companies find out too late in the process that some things were not done according to FDA expectations as described in the various guidance documents and then try to use a Band-Aid approach. It is important to have input from all departments within the company from the earliest stages of development to prevent mistakes,” says Agrawal.

	
	One of the important tasks that most regulatory agencies worldwide perform is facility inspections. Companies that operate in the United States or import products into the US are inspected by FDA. An FDA spokesperson states, “During an FDA inspection, investigators are seeking to verify that facilities are operating in a state of sufficient control according to current good manufacturing practice (CGMP) guidelines.” 

	Companies that operate worldwide should be aware of the various regulations and what international inspectors might be looking for during an inspection. “Although there is a common approach for regulatory inspections by all agencies that are members of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) in the US, European Union, and Asia, their focus and expectations may differ. For example, some agencies might look more closely at pest control, whereas others may be more concerned with adherence to local pharmacopeias. In addition, agencies such as the US FDA will investigate potential criminal conduct, while other agencies verify compliance with the regulations,” says Siegfried Schmitt, principal consultant at PAREXEL. 

	Facility inspections by regulators may cause anxiety for pharmaceutical companies, but being prepared can make the process pain free. “The best way to prepare for an inspection, whether it is in the US, EU, or Asia, is to know your operations, understand your quality system, understand your investigations, and follow your standard operating procedures (SOPs),” says Schniepp. Personnel should be prepared and relaxed and, according to Schniepp, employees should not “change their behavior to accommodate the regulators.”  An FDA spokesperson concurs, “To prepare for an FDA inspection, facilities should review the CGMP guidelines and assure they are in compliance with those guidelines. FDA offers several resources to help facilities better understand and adhere to CGMP guidelines, such as public outreach through presentations at national and international meetings and conferences to explain the CGMP requirements and latest policy documents.”
	According to David Lerner, life-sciences expert with the PA Consulting Group, there are a variety of things pharma companies can do when preparing for a regulatory inspection, including having good controls, processes, training, and systems up front. “There is simply less preparation effort if the company is in a good compliance state,” Lerner says. Chris Moreton with FinnBrit Consulting agrees, “[Companies should] make sure everything is done correctly day in and day out. Make sure that the SOP system covers all the activities needed to undertake the type manufacturing operations at the site.” Schniepp agrees that preparation is key. “The biggest mistake companies make is not being ready for an inspection. The best rule of thumb to follow is to be ‘audit ready all the time’.”

	Madsen suggests performing internal audits prior to an inspection by regulators. “Internal audits … may be helpful in identifying areas that may pose problems during the inspection,” says Madsen. Practice audits can challenge logistics and allow personnel to go through an ‘inspection’ without the pressure of an official inspection, according to Schniepp. “You want [personnel] comfortable and unflustered when the regulators are viewing them performing their jobs or asking them questions about their job functions. During the actual investigation, the best way to make the impact on your employees pain free is to make sure you talk to them before they enter into the inspection room or before they are to be observed by the inspectors. This is not to coach them on what to say but rather to calm them down before they are observed or questioned by the inspector so they can interact in a positive way with the inspector,” she says.

	Companies should also identify and address risks prior to inspections, according to Lerner. “Knowing your risks allows you to better prepare for inspection questions.  You also need to be seen as addressing the risks that you have found,” he says. 

	Companies should plan the logistics of an inspection including the location for the inspection, personnel escorts and contacts, and preparing any communications or documents the inspectors might require. According to Schniepp, inspectors may want to see “a copy of the current organizational chart, a copy of the titles of your SOPs, a list of your corrective actions and preventive actions (CAPA)/investigations, and a list of your complaints. The rule of thumb is to go back approximately two years for the CAPA/investigations and complaints.” Addressing findings from previous inspections is also imperative. “Inspectors review previous inspection reports and expect that prior commitments have been completed,” says Lerner. Most importantly, any documents the inspectors ask for should be provided in a timely manner. “Bottom line, the sooner you get the regulators the information they want, the sooner they will be able to wrap up the inspection. If you are organized and forthcoming in your information your inspection will go much smoother,” says Schniepp.

	Lerner suggests that companies may benefit from providing inspectors with an overview of their facilities and processes. “Recognize that the inspector is dropping into your environment with little context. By providing them with the context they will be better able to understand what you do and ask better questions.” Lerner recommends using storyboards to describe processes, situations, or decisions. “Storyboards are useful because they help the inspector understand the situation rather than forcing the inspector to pull information from one or more documents,” says Lerner.

	While preparation may be key, there are obvious things companies should avoid doing during an inspection, such as lying, being evasive, or arguing with inspectors. “The inspector will want direct answers to direct questions and to talk to the people doing the job, not management,” says Lerner. The regulatory investigator is there to ensure GMPs are being followed, and avoiding the inevitable may make things worse. “Sometimes companies try to hide situations from investigators or provide misleading answers.  A good investigator usually asks the same question in different ways and in multiple areas and will uncover misleading or untrue answers,” says Madsen.

	Responding to violations observed during an inspection is equally important. “Respond quickly but thoughtfully.  For a 483, point out any situations that the investigator may not have fully understood.  It’s best to clarify and resolve these during the inspection, if possible, before they are put in writing,” says Madsen.

	Lerner suggests that companies take FDA 483 observations seriously, but be careful not to overcommit. “When the inspector returns, they expect the commitments to be completed and could escalate actions if not completed.” Systemic corrections should be put in place, says Schniepp. She advises that companies “make sure you address how you are going to maintain a compliant status once the change has been implemented.” Moreton suggests that companies have a plan for any violations that cannot be immediately fixed. 

	Addressing root causes of observed violations is key, according to Lerner. “The agency really wants to see that you are addressing the root cause and that you are addressing this issue across the organization. As an example, if the inspector found that a particular non-conformance (NCR) was not investigated fully, it is equally important to both explain what happened in that instance (and why you made specific decisions) and what you are doing to prevent future insufficient NCR investigations.”

	Properly addressing violations cited by investigators on a FDA 483 form may help companies avoid receiving a warning letter from FDA. When FDA does send a warning letter, companies should take their response seriously. “The warning letter itself is an indication that the company has been out of compliance for some time and has been unsuccessful in solving their compliance issues. Probably the most conservative response to a warning letter is to outline your plans to improve your quality system and commit to bringing in an unbiased third party (consultant) to review and make sure your plans are executed appropriately and will eliminate your systemic quality problems. If you are at the warning letter stage, it means you have been unable to solve your problems and you need help. Make sure you communicate this in your response,” says Schniepp. This advice rings true. In recent warning letters, the agency has often suggested a company obtain outside consultation in resolving GMP violations.

	Ensuring the safety and efficacy of medicines doesn’t stop when the drug is approved by regulators and distributed to the public. Inefficient manufacturing practices, GMP violations, negligence by ingredients or service suppliers, and other complex issues can all have an impact on the safety of a drug product. Both industry and regulators have a continued responsibility to ensure the safety of patients.

	One aspect of pharma’s part of this responsibility is keeping regulators informed of any adverse events associated with a drug product. An FDA spokesperson states that pharmaceutical companies that “market prescription and nonprescription drug and biological products in the US must review all adverse event information they obtain or otherwise receive from any source, and report adverse events to the FDA’s Center for Drug Evaluation and Research as described under the regulation or section of the Food, Drug, and Cosmetic Act that is applicable to the type of product they market.”

	“Adverse event reporting is a serious matter and should not be taken lightly,” says Schniepp. A well-managed and properly staffed pharmacovigilance unit is key, according to Moreton. “[The unit should have] clearly defined responsibilities and report in to the senior management (not sales and marketing),” says Moreton.
	“Companies should report adverse events within the deadlines established by the regulatory authorities. When in doubt, it is better to be conservative and report by the earlier of multiple deadlines. Providing complete and accurate information is important as is maintaining complete and accurate records. It is best to initiate the process for adverse event reporting as soon as the company becomes aware of it to prevent any delays in filing,” says Agrawal. Schniepp agrees, “The most common mistake is waiting too long to report the event. Many companies are tempted to wait until they have completed the investigation into the event before reporting its occurrence.”

	FDA is clear on adverse event reporting. “These entities must ensure that the adverse event reports they submit to FDA are transmitted in an electronic format the FDA can process, review, and archive.  In addition, these entities must have written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse event to FDA as well keep records of all known adverse event information,” states an FDA spokesperson.

	Regulatory agencies should be used as a tool to help manufacturers develop and market their products and that regulators and their regulations should not be feared or avoided. Being mindful of regulatory requirements before and during development will make the regulatory approval process smoother, and maintaining GMPs and having well-trained personnel will ease the stress of regulatory inspections. 

	It is clear that both industry and regulators have the same ultimate goal: provide safe and effective treatments to people who need them. Understanding and nurturing the industry-regulator relationship fosters innovation and ensures patient safety worldwide.  

	When referring to this article, please cite it as S. Haigney, "Nurturing the Relationship Between Industry and Regulators," 

Pharmaceutical companies must see regulators as partners in their efforts to provide safe and effective therapies worldwide.

Nurturing the Relationship Between Industry and Regulators

 reached out to the US Pharmacopeial Convention (USP) to get an understanding about how pharma manufacturers can get involved in developing industry standards.

 How can pharma companies work with USP to help develop standards and monographs?

 Pharmaceutical companies can work with USP in the following ways to participate in the development of standards and monographs:

		Donations: Companies can donate product specifications, analytical methods, and other procedures to help advance the development and revision of USP standards. Companies also can donate bulk materials as candidates for the development of physical reference standards.

		Volunteering: Industry experts are invited to apply to participate in the decision-making and advisory bodies that set USP standards.

		Feedback: Industry is encouraged to review and provide comments on proposed standards revisions via Pharmacopeial Forum, as well as participate in USP Workshops, Stakeholder Forums, and other events.

 Are there USP programs addressing health crises or unmet needs with which companies can get involved?

USP advocates for quality standards around the world. We work through global partnerships, regional networks, and capacity-building programs to help regulators strengthen drug surveillance systems in order to combat counterfeit and substandard medicines. Highlighting one program in particular, USP’s new Global Health Monographs address essential medicines that have a major health impact (e.g., malaria) or are used to treat neglected diseases in underserved communities outside of the US. Pharmaceutical companies can get involved by donating specifications and materials for the development of Global Health Monographs.

 Are there harmonization programs companies can participate in?

 USP encourages companies to participate in its harmonization efforts by reviewing and commenting on proposed harmonized standards that are published in USP’s free online 

. Product innovators can work with USP in advance of losing their exclusivity to establish a standard that can be harmonized with other pharmacopeias. Interested parties can also view information about standards currently being harmonized as well as those that have completed the process on 

Pharmaceutical Technology reached out to the US Pharmacopeial Convention (USP) to get an understanding about how pharma manufacturers can get involved in developing industry standards.