Background
After 45 years in the drug and API industry, I have seen and experienced many things both as a member of the FDA’s regulated industries and as an active participant and I trust, contributor to the development of policies and practices used to positively impact our society and the Good Manufacturing Practices and other standards that are used for Active Pharmaceutical Ingredients (API), excipients, drug products, and other regulated materials.
I feel it is time that I share my personal views on what is happening or not happening in a number of industrial and regulatory areas. History tends to be a good educator if one takes the time and interest to learn from it. Both regulators and drug firms have a responsibility to assure that high quality materials and products are used and manufactured for the public’s consumption. However, as we all know, there have been too many instances of both industrial and regulatory failures which have caused illnesses and even death. All of which were most likely preventable or could have been minimized if proper actions were taken or illegal acts were discovered early enough.
Over the years, too many people have been adversely affected from dangerous compounds or substances being present as an impurity or contaminant present in an API, excipient or even foods and food/ nutritional supplements. Their presence can be derived from intentional or accidental practices or actions. Indeed, low level impurities and contaminants present in API, excipients, or nutritional ingredients/ supplements have left their mark on people. Some causes of these problems appear to be intentional acts probably driven by profit motives, some occur because of poor procedures being used, and there are always some that happen because of unexpected conditions. Until something happens to highlight a risk, potential dangers can go undetected. In theory and in the perfect world, all risk would be eliminated through an ideal development program that has identified and removed all unacceptable conditions and components of a product. However, this is not a perfect world and some risk will always exist. What can be done to reduce or mitigate this possibility, needs attention from both industry and regulatory agencies such as FDA and maybe, for the USA, Customs agents. It may even be time for new legislation that will reduce the public’s risk to imports that are not properly labeled or controlled as to when and where they are produced, packaged and labeled.
There has always been a tendency to either do too little because it is too costly to address, or do too much as an overreaction. The most disturbing approach is to enact requirements that merely pass the responsibility to another party while governments do nothing to help mitigate the problems. Equally disturbing is when firms don’t do the right thing and leave the problems to be remedied by the government or regulatory authorities. In my opinion, both industry and regulators carry significant responsibilities in addressing such issues. Governments have to cease passing laws that go unfunded or pass responsibilities inappropriately to the private sector. Firms must take responsibility to assure that what they buy and do is appropriate for the products they purchase and produce.
Early in my career, many firms would produce the API or intermediates they needed for their own products. Even when this was not possible, the materials were usually purchased from a very limited number of manufacturers and locations. Whenever possible, these producers were usually local as the global economy as we know it today did not exist. Indeed the world today is very different from forty or fifty years ago and things need to change to reflect the loss of control that came along with this decentralization of manufacturing and supply.
Options to Consider by all parties
In this changing world, what worked historically may no longer be effective. Practices, requirements, rules and regulations need to evolve with conditions that modify over time. This evolution is a necessity in order to protect the public, permit industry to work effectively and efficiently while producing high quality products under GMP conditions. The Global economy, major expansion of supply chains, and mufti-national, and mufti-location sourcing of API and excipients all create a need to rethink what firms and regulators need to do to assure proper compliance levels. Below, I will discuss some issues that are currently being discussed and considered by FDA, Congress, and industry in various different forms. This discussion includes my opinion as to what I think about the subject!
Mandatory On-site Audits of Suppliers
Auditing of suppliers is not a new concept. However, in this changing world the mode or methods used for these audits needs attention. There are a number of ways to look at suppliers. One is to accept a certification from an internationally recognized organization which can certify a level of conformance to Quality Standards established by the organization. This is usually performed by other parties authorized to perform such reviews. Another approach is to use other recognized organizations, governments or regulatory authorities or groups that can perform other quality reviews which are recognized as reliable. Lastly is to rely on the previous approaches and supplement them with a periodic audit by the purchasing firm. I strongly suggest that this last approach be the only reliable approach to use. The on-site review of a supplier cannot be ignored by a purchasing company. This extra, more random examination by the drug (API or Dosage form) company can go a long way in reducing risk and when it is done by the drug firm itself, or an auditor hired to perform a specific audit for the drug firm, is more focused then one would get from any certification group or organization.
Producers of drugs, whether they are drug products or API, should all have comprehensive programs for performing on-site audits of any critical API, intermediates, or component operations that are important to the quality of the product they will be manufacturing. While many firms have supplier review activities, not enough have instituted sufficient on-site auditing to assure that conditions and practices at their suppliers do not expose the products they purchase to inappropriate conditions or processing. Paper reviews can only provide a very limited protection. One needs to go out and observe conditions and procedures being used.
If firms don’t adopt this added responsibility then it is, in my opinion, appropriate for FDA to issue revisions to regulations that will obligate drug manufacturers to conform to such a requirement. On the other hand, FDA must be held accountable for materials, API, excipients, and other food, drug, and cosmetic products allowed into the USA for consumption by its citizens. Just because manufacturing has migrated outside of the USA, the authority and responsibility of FDA should not be diminished. Congress will need to provide the authority and resources necessary to close this very dangerous loophole.
In my opinion, if resources and costs become a critical issue, products not properly reviewed at their sources should be prohibited from entering into our economy. The decision to move manufacturing outside of the USA was financially driven and the same conditions may drive firms to rethink from where and from whom they purchase materials and products. Of primary importance is that Quality materials and products are being purchased and used as part of the drug supply chain and this includes inactive components of drugs (excipients). Governments and industry need to find a way to assure product quality with a real level of confidence. International trade or not!
Contrary to current practices, random, unannounced audits are the only real effective way to monitor suppliers. While this causes inconveniences and increases costs, this approach helps greatly reduce inappropriate or even illegal practices from occurring. Domestic inspections are unannounced for this reason and foreign inspections or audits should operate under the same rules. Regulators and firms need to find an agreeable way to perform such reviews. I know this is a real challenge, but a realistic way to accomplish this spontaneity is fundamental to discovering weaknesses and deficiencies.
Greater Control of Imported Materials at Borders – Governments Need to Use Their Authority
FDA or another authorized federal agency must be held responsible for the materials entering into this country. The point of entry of materials and products into the USA has to be improved. In this era of computerized systems, a more effective control system has to be implemented which will not allow entry into this country, of products or materials that have not be properly authorized and accepted as safe.
This is easy to say, but difficult to do. International commerce is indeed a complex subject and there are many complexities to consider, but one thing is for certain: We need to stop potentially defective or adulterated products before they enter the supply chain. Has anyone seen any antifreeze containing toothpaste lately?
Improve Analytics Used to Control Products – Something is Better than Nothing
It is impossible to analyze for every possible contaminant. To suggest that would be absolutely unrealistic. However, as technology continues to improve we will get closer to that ultimate goal. While the world waits for this ultimate goal, no materials or products should be accepted for use in FDA regulated products without comprehensive testing that is capable of identifying the material and its potential purity or impurities. Even a general screening test to verify that a delivery is similar in composition to previous deliveries is better than nothing.
Make Changes to Labeling Requirements of Imported Goods – Every Purchaser must be able to determine the Manufacturer and the Plant/Location of the Source.
The time has come for firms to have no doubt about who made a material and where it was made. This is the first important step in tracing materials through a supply chain.
Start with simple requirements. For example, one of the recommendations that came out of the Haitian Workgroup that reviewed the deaths from the DEG contaminated glycerin was to require all labels on products to not only include the country of origin, but the manufacturing firm and the location of the production facility. This relatively simple requirement would make it easier to control imports from acceptable facilities and firms.
FDA Should be Required by Law to Increase its On-site Inspections Overseas – Stop Ignoring this Responsibility.
While FDA contemplates requiring firms to increase their audit of their suppliers, the FDA itself can no longer be allowed to continue its primary inspections to focus on domestic locations and perform only limited foreign reviews. We are now in a truly international supply situation and the FDA, with the support of congress must greatly increase its foreign inspections. This does not mean to just open foreign offices but to actually perform inspections at reasonable intervals to assure that the supplies coming out of those facilities are proper, following GMP, and not exposed or contaminated with substances due to conditions or practices that are inappropriate.
FDA can Improve Industrial Relations to the Benefit of the Public
For years, FDA has had the tendency to take information provided by firms and report such information as found by agency personnel and not voluntarily provided by the company. When is the last time you have seen, if ever, the agency report problems in their reports, FDA-483 or Warning Letters even suggesting that the information cited was voluntarily provided by a firm and that the firm has already initiated or implemented corrective action? Instead, in most cases FDA personnel tend to take such information and cite the problem without ever giving credit to the firm for discovering and initiating corrective actions. This approach has always contributed to reluctance on the part of industry in proactively sharing information unless they were obligated to provide such information. A change in regulatory attitude and approach will go a long way in opening up communication channels between FDA and industry. Don’t misuse information provided by firms to abuse and embarrass firms. Most companies want to do the right thing. Such a change in approach and attitude can go a long way in protecting the public without more regulations and legislation.
Under such an improved environment, failure to share information with FDA and take appropriate action, should then be strongly criticized and even condemned.
FDA can’t take Forever to Address Issues and Expect Industry to Completely Address Complex Investigations Quickly.
Real world solutions, which appropriately focus on regulatory expectations, need to evolve. Presently, one pharmaceutical manufacturer is being condemned for not fully investigating and completing reports for as much as a year. My guess is that the real story is that it may have taken up to a year to determine there was a real issue, determine what the likely cause was and to develop corrective actions. Why so long? Firstly, complaints usually come into a firm slowly and randomly. If that in fact is not the case, then I would agree that the referenced time period is excessively long. Next, there is a need to determine if there is a real risk associated with the reported problem. This is another step that may not be able to be conducted quickly. Lastly, implementing appropriate corrective actions, without factual information about the cause is almost impossible for anyone to execute properly. FDA should expect and indeed be notified quickly, of important events that impact products in the field. When FDA believes faster or different action should be taken by firms, they should promptly discuss their suggestions with the company. Both should agree upon a plan that is acceptable and possible to implement. Historically, FDA has always been willing to discuss, either at District Offices or at FDA Headquarters, concerns raised by a company provided the meeting is requested by the business. What needs to change is that FDA should take the initiative and move quickly by informing a company they have additional concerns and suggestions, and rapidly put their thoughts on the table for discussion and consideration by the firm. Also, FDA needs to recognize real-world time elements that impact plans and schedules. If a serious risk exists, withdrawal of product from the market is the prudent immediate action.
FDA Needs to Become Part of the Solution.
FDA rarely offers advice on how to proceed even if asked by industry. This situation must change. This agency has a very large professional staff, technically competent, and well educated that would usually rather condemn than participate in the solutions. Perhaps FDA needs to take some hints from other Federal Agencies that establish recommendations following their investigations. Such an approach may better serve the public interest than criticizing what firms do, how long it takes them, and the lack of communication with the agency. It is a very rare inspector or compliance officer that makes realistic concrete suggestions for corrective actions that can be achieved within a practical time period. Unless this changes, there will always be a tendency for an adversarial relationship.
FDA Needs Absolute Authority to Recall Unsafe Products. However, . . .
From my experience, I have never seen any responsible firm refuse to recall a product that FDA has deemed or considered unsafe. Not being privy to all situations encountered by FDA, I would think that such authority may be of value. However, I do think that such legislation should also mandate that FDA become a part of the solution in developing corrective actions. It is easy to remove products from the market without an obligation to help address possible corrective actions. If this is allowed to occur, the American public may ultimately find itself without lifesaving drugs that are all in quarantine because of unknown or unevaluated issues that have no realistic way to be resolved with regulators that are not also responsible to help fix the problems condemned by them.
FDA Should Have Full Authority to Access all Manufacturing, Control, and Complaint Records.
In my opinion, if this authority does not exist for all FDA related industries it should be given that authority. Without it, FDA cannot determine compliance levels. The only restriction to that authority should be free open access to self-audit findings. If this currently self-imposed restriction is removed, and FDA examined these internal documents, there would be an incredible undermining of self-audit programs that are valuable for industry to continue to perform. Reason: As mentioned above, FDA without a change in approach would use the data contained in those report to condemn firms and this action could lead to increased public liability proceedings.
FDA Should Make a Matter of Public Record:
What sites, both foreign and domestic, FDA inspected and whether the facility was found acceptable, acceptable with correctable deficiencies, or unacceptable for continued distribution of the products from that facility. If the facility is foreign, the products should not be permitted into the USA.
Conclusions
I have shared my thoughts about some trends and discussions being examined by government and industry for application to drugs and related industries. I know there will be those that disagree with my stated positions, as well as individuals that will support my suggestions. What is important is to give proper consideration to conditions that need attention by society!
When things go wrong, there is always a call for greater government control and regulations. Sometimes the call is justified; however, the revisions imposed can be unsuitably applied and actually create problems of an even greater nature than the issues that existed before the new regulations or legislation existed.
First identify the problems correctly, authorize the appropriate level of responsibilities, provide adequate manpower and funding for the task, and demand cooperation from all parties. This should include authority to stop products from entering the USA if FDA has not reviewed its manufacturing environment in the foreign country. Failure to cooperate with FDA should then be subject severe legal action after adequate attempts to resolve these issues are placed on the table for discussion and resolution.
Enforcement responsibility and authority for FDA should be unquestionable. Its use of these need to be part of a new direction and environment which makes them part of the solution and not part of the problem. They should be required to provide suggested corrective actions which they will support in the spirit of getting fast, but yet reasonable corrective actions implemented. Then we may see a reduction in most every problem, except intentional criminal adulteration of products which poses an entire set of other problems for regulators and the public alike.
References
1. “DRUG SAFETY REFORM”, Chemical and Engineering News; June 21, 2010; Government & Policy; pages 22-23.
2. “A Word to the Unwise”, Hoffman, Michelle, Editor-in-chief Pharmaceutical Technology; July 2010; page 12.
3. “Washington Report”, Pharmaceutical Technology; July 2010.
Max Lazar retired from Hoffmann-La Roche, Inc. in 2001 after 35 years, where he was Vice President, FDA & DEA Compliance. In that position he was responsible for compliance oversight of all of the Roche USA businesses including Active Pharmaceutical Ingredients, Pharmaceuticals (Solid, Liquid, and Sterile), R&D, Diagnostics, Fine Chemicals and Vitamins. Following his retirement, he established a consulting business specializing in API GMP issues and the training of personnel covering the ICH Q7A Guidance. As a voting member of the ICH Expert Work Group (EWG) that developed and negotiated this new international standard, Max is uniquely qualified to share and explain the EWG’s intent of this new guidance. His involvement in this new API GMP pre-dates the ICH activity itself.
His more than 40-year career in the Pharmaceutical Industry includes numerous memberships and chairs of committees. He founded and chaired the Pharmaceutical Manufacturers Association’s Bilk Pharmaceutical Committee of the Quality Control Section. This chair lasted through the reorganization of PMA into PhRMA and until Max’s retirement in 2001. He has presented at numerous meetings and training programs including SOCMA, PDA, DIA, PhRMA, Barnett, and IIR both domestically and overseas.
Max was named Topic Leader for the Pharmaceutical Research and Manufacturers Associations ICH Q7A team that developed the API GMP document for ICH. He represented USA industry at the PIC/S Canberra Conference which preceded the ICH API activities and worked with FDA during the 1980-2000 era addressing all of the API industry-related regulatory issues including the 1987 NDA re-Write Guidelines and GMP activities. He was one of the five invited industry representatives at the WHO/CDC/FDA Dethylene Glycol Contamination Prevention Workshop that followed the Haitian tragedy where almost 100 children died. This workshop developed recommendations for consideration by the Pan American Health Organization and WHO. Max was named as PhRMA’s representative on the FDA PQRI initiative that developed the initial Bulk Substance projects.
He was Vice Chair of the USP Pharmaceutical Waters Expert Committee (2000-2005) and has been re-elected to another five-year tern (2005- 2010) as a member on this USP Expert committee. He conducts training and consultations on API GMP and other FDA Compliance issues. While specializing in API, Max’s experience provides him with expertise in many areas of FDA compliance including laboratory, documentation, sterile and oral dosage forms as well as devices, diagnostics and radiopharmaceuticals.
For his contribution to Q7A, he was awarded the USA FDA Commissioner’s Special Citation “For outstanding cooperation and achievement in developing an internationally harmonized good manufacturing practice guidance for active pharmaceutical ingredients used in human drug products.”
He is a member of numerous professional organizations. Max is listed in numerous editions of Who’s Who including Who’s Who in America and is a graduate of Brooklyn College of the City University of New York. He has contributed to several books dealing with APIs, and has written and published several guidances covering Bulk Pharmaceutical Chemicals as chair of the PhRMA and PMA Bulk QC Committee and Workgroups. He resides in Surprise, AZ.
The author can be contact at [email protected]