European regulations require that batch release testing be conducted in Europe for products marketed in the territory. Therefore, it is important for companies outside Europe to understand how these requirements affect the outsourcing of batch release testing, including the function of mutual recognition agreements, the role of the Qualified Person, and the extent to which these requirements apply to clinical trial materials.

One of the many drivers for a company to consider outsourcing is geography—the need to have a particular piece of work conducted within a specific country or regulatory region.  

Companies may first encounter this need if there are potential patent issues surrounding the products they are developing. In some countries, most notably the US, developmental work is subject to patent restrictions that in other countries would only apply when the new manufacturer sought material gain, i.e., when it is ready to market a product. A new manufacturer of a follow-on product would thus wish to conduct any work, outsourced or otherwise, in a country where it would be free from potential suits. 

Later in product development, it may be necessary to conduct clinical trials in specific patient groups or ethnicities, which may be accomplished most easily by conducting some of the trials in particular countries. It may also be necessary to conduct clinical trials in a particular country before marketing authorization will be granted in that country. 

The final stage where the location of the work can become relevant is in release testing, the quality control testing of each batch of finished product. This situation is particularly relevant for biological products for which a single manufacturing site is normally used for global supply, whereas for small-molecule products, multiple manufacturing plants located in local markets are more common. In the European Union (EU), there is a regulatory requirement that each batch of a finished marketed product be tested in the EU against the approved product specification. There is no requirement for the product to be manufactured in the region, but non-EU manufacturing sites are subject to inspection by the EU authorities. For companies with no testing facilities in the region, the EU marketing of their products will thus require outsourcing to a EU-based facility. The purpose of this article is to review this requirement and provide guidance to manufacturing companies that need to outsource this testing. 

When considering Europe as a market for a pharmaceutical product, one first must define what is meant by 

 The geographical region and regulatory groupings do not match; whilst the former is fixed, the later is subject to extensions as the political situation changes. 

The top half of Table 1 lists the countries that are currently members of the EU. All legislation passed at the EU level applies to these countries. For pharmaceutical products, the regulations are administered by the European Medicines Agency (EMEA). EU legislation is issued in the form of directives from the European Commission (EC) to all member states (countries). Then each country must implement the directives through its own legal framework within a given time period. 

Table 1. Countries of the EU and non-EU members of the European Economic Area 

For pharmaceutical products, there are three main directives of relevance to testing requirements:  

Directive 2003/94/EC lays down the principles and guidelines for manufacturing practice for medicinal products for human use and investigational medicinal products for human use.

Directive 2001/83/EC is the Community code relating to medicinal products for human use and sets out the requirements and procedures for obtaining marketing authorization.

Directive 2004/27/EC amends Directive 2001/83/EC. 

 Directive 2003/94/EC is supplemented by "The Rules Governing Medicinal Products in the EU, Volume 4, EU Guidelines to Good Manufacturing Practice."

Point 39 of Directive 2004/27/EC replaces the text of article 51(b) of the original medicinal products for human use Directive with the following text: 

In the case of medicinal products coming from third countries, irrespective of whether the product has been manufactured in the Community, that each production batch has undergone 

 a full qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks necessary to ensure the quality of the medicinal products in accordance with the requirements of the marketing authorisation.

It is this statement from the directives that requires that a company wishing to market its product within the EU have testing conducted on every batch of that product in one of the 27 EU member countries. 

Other Locations for Testing: Mutual Recognition Agreements

In addition to the EU, there are other political and economic groupings in the geographical region of Europe. The directives and the decisions of the EMEA are also agreed to by the European Economic Area (EEA); which comprises the EU member states plus the three additional countries listed in the bottom half of Table 1. Testing conducted in these three countries is also acceptable for product release in the EU. 

A third mechanism exists to allow testing conducted outside the EU to be accepted: mutual recognition agreements (MRAs) covering good manufacturing practices (GMPs) for the product under consideration. The current status of EU MRAs covering GMPs is shown in Table 2.  

Table 2. EU good manufacturing practice mutual recognition agreements (MRAs) 

Thus, if a medicinal product is to be marketed in Europe (i.e., the geographical region comprising the 27 EU member states plus Iceland, Liechtenstein, Norway, and Switzerland, it must be tested against the EMEA-approved specification in one of the 33 countries with fully operational agreements (if it is a blood-derived biological product) or 34 countries (if it is not a blood-derived biological). Biological products tested in Japan or any form of pharmaceutical product tested in the US must be retested. 

Testing conducted in Europe is accepted in the US, provided the testing facility has been approved by the US FDA. Many companies thus consider basing worldwide testing capabilities in Europe to minimize the need for repeat testing. For the rest of this article, the term 

 will be used to refer to the 27 EU member states, plus Iceland, Liechtenstein, Norway, and Switzerland. 

The provisions of article 20(b) of Directive 2001/83/EC as amended by point 18 of Directive 2004/27/EC allow the batch testing noted above to be contracted out to third parties provided the laboratories have been verified by the competent European authorities. Laboratories used for contract testing may be located in any European country or any country with a relevant MRA. European-based contract laboratories offer this service to virtual companies using contract manufacturing organizations based outside the region and to larger companies that do not possess the facilities or capacity to conduct the testing themselves. This is particularly true for biological products for which testing capacity is often located at the single site performing the worldwide manufacture, frequently in the US. 

The facility that will conduct European batch release testing must be identified in the marketing authorization application (MAA) for the product. Therefore, if a company will need to outsource batch release testing, it must start the process of laboratory selection well in advance of the intended product launch. This selection process will follow the usual procedures for choosing an outsourcing partner, such as questionnaires, audits, and bid proposals, but also must include an assessment of the laboratory's accreditation under European GMPs and its suitability to handle the particular product type and its analytical tests. 

Once the laboratory has been selected, the process of method transfer can start. The methods and specifications that will be used by the contract laboratory will be those detailed in the MAA; the manufacturer must maintain control of these documents throughout the testing period because any change made by the contracting laboratory could require regulatory approval. The first stage of maintaining this control is for the manufacturer to add the contractor to its in-house circulation list for methods and specifications. Thus, if any revision to these documents is required by the manufacturer, the revised document is automatically circulated to the contractor to ensure that it is using the current version. The timeliness of this circulation is critical.  

Next, the contractor must have established procedures for preventing any deviation from the methods as supplied. If local instructions are needed by the contractor, for example to allow alternate suppliers of reagents, these instructions must require approval by the manufacturer.  

The method transfer process itself can take a considerable period, potentially longer than the MAA review if complex, specialized assays are necessary. Establishing banks of cells required for 

potency testing or the purchase and validation of specialized equipment and software can be particularly time consuming. The partnership between the contract laboratory and the manufacturer must ensure that sufficient staff are trained to perform all the batch tests within the required time period throughout the year. This can be accommodated in the initial transfer, or an initial pool of staff can be trained with cascade training as the marketed batches start being tested. Whatever the approach, cascade training will be required during the lifetime of batch testing; there will be staff turnover and hopefully increasing market share for the product will mean more batches will require testing. Managing this cascade training is essential to ensure that there is no drift in the application of the methods. 

Technical and quality agreements are a requirement of European GMPs, but the documents often are used to cover business aspects of the relationship as well. Agreements between the parties must define delivery notice periods and turnaround times for reporting results. The lines of communication, particularly for unexpected or out-of-specification results and deviations, must be clearly stated.  

The agreement must be long term in nature, to protect both parties. For the contractor, a substantial commitment in resources will be made for the routine testing of batches, and a standard termination clause may not give the contractor time to replace the work. For the manufacturer, changing the testing laboratory would require an amendment to the MAA, so the termination clause must allow sufficient time for the manufacturer to do that. It is thus important to reflect the nature of the business in the termination clause. The agreement also must have a built-in review mechanism and establish a maximum period between reviews. 

In addition to requiring that batch release testing be conducted in Europe, the European GMPs require that the samples used for batch release testing be taken from the bulk shipment on European soil; sampling at the manufacturing site outside Europe and sending the samples separately to the testing laboratory is not permitted. The manufacturer must thus have a mechanism for sampling at the importation site or distribution center in Europe.  

The importer must have a Qualified Person (QP) named on its authorization. The QP has a role defined in European GMPs and is ultimately responsible for releasing each batch of the product onto the market. The QP is required to review all manufacturing records and testing results for the batch to ensure the quality of the product. Provision must be made in any agreement with a contract testing laboratory to ensure full notification of the QP of not only the results but also of any problems with the conduct of the testing. 

Directive 2003/94/EC states in article 11: 

When the (investigational medicinal) products are imported from third countries, analytical control shall not be mandatory.

The conduct of clinical trials in Europe requires that investigational medicinal products (IMPs) be manufactured and labeled under conditions that meet the requirements of European GMPs, taking into account the developmental stage of the product. As with licensed products, the final release of the IMP for trials in Europe is conducted by a QP. In the clinical trial situation, however, the QP may have to conduct some assessments on a case-by-case basis because the manufacturing and distribution of the products is not as well established as would be the case for a marketed product. For example, although the regulations do not require batch release testing in Europe for an IMP that has been manufactured and tested in a third country, the QP may request that retesting be conducted to verify that there has been no harm to product quality during storage and distribution. European regulations recognize QPs for IMPs as a separate class of QP owing to the differences between the type of data and situations reviewed for IMPs and fully authorized marketed products. 

Analytical methods for IMPs are not validated to the same extent as those for licensed products; the potential comparability of results from retesting to those generated by the manufacturer must be realistically assessed when considering the benefit of retesting. 

The labeling of IMPs for early-phase clinical trials often is conducted at the trial site. If a product is shipped in an unlabeled form, the potential for mix-up is increased and a QP may well request limited testing (e.g., identity, protein concentration, or some other quantitative measure if multiple dose strengths are involved in the trial) on receipt at the labeling site. 

The requirement of European legislation to have every batch of a marketed medicinal product tested on European soil creates the need for a company to have a testing laboratory in the European geographical region. If a company does not possess such facilities, the testing will have to be outsourced. Contract facilities in Europe recognize this need and provide the service to non-European based manufacturers through long-term agreements to the mutual benefit of both parties.

Articles

A good understanding of European regulations governing batch release testing will facilitate your collaboration with a contract laboratory.

Batch Release Testing: A Geographical Driver For Outsourcing in Europe

Following cases of mycoplasma contamination in the 1970s, endotoxin concerns in the 1980s, and bovine spongiform encephalopathy (BSE) scares in the 1990s, the biopharmaceutical industry continues to push for thorough and transparent information about the origin of raw materials used in the manufacture of therapeutics. In particular, companies often ask cell culture media suppliers for documentation of the animal-origin free (AOF) status of media and reagent components. Many biotherapeutics manufacturers have begun applying varying definitions and standards of AOF, however, depending on the regulatory authorities they work with and their own level of concern; many companies also have begun to demand detailed information about the complete supply chain of components used in media and reagents. The consequences of these in-depth investigations can be significant in terms of the cost and availability of materials. To help navigate what is possible and practical, this article reviews the levels of inquiry required for selecting AOF cell culture components; how to qualify and validate the claims; and finally, ways to help balance risks with patient safety without affecting product availability.

Concern about the risk of animal-derived transmissible spongiform encephalopathies (TSE) has long been a driver for biopharmaceutical companies to eliminate animal origin (AO) materials from their cell culture processes.

  This trend has prompted research by manufacturers of cell culture media into producing media that can maintain productivity without using animal-derived serum, proteins, or lipids.

  To reduce the risk of known contaminants such as BSE and yet unknown agents, biopharmaceutical companies are pushing cell culture manufacturers to take increased levels of care in choosing raw materials for their products.   

(AOF) generally is used by cell culture component suppliers to refer to any components not directly derived from eukaryotic animals (excluding higher plants, fungi, protozoa, and algae). This level of animal-origin free is known as 

. Currently, there is no standard industry definition that addresses the status of the lower life forms listed in the animal kingdom (e.g., sponges, worms, insects), although some biopharmaceutical companies define an animal source as any multicellular form with specialized eukaryotic cells that have their own means of locomotion. This raises the question of what the definition of 

In addition, media suppliers are now being asked to provide cell culture media in which all the components of the cell culture media meet the standard of 

 This term has no universal definition, but for the purposes of this article, secondary level AOF will be used to refer to media components that have been manufactured without the use of products derived directly from animals. For example, if a protein component has been manufactured using recombinant 

 grown in a culture containing no animal-based peptones, the component is classified as secondary level AOF.  

As suppliers and manufacturers have gained a better understanding of the media manufacturing process and how to remove AO components, the desire has emerged to go even further. The most challenging standard of AOF is the tertiary level, which requires media manufacturers to ensure that none of the components used to manufacture the raw materials are derived from an animal. In practice, this would mean that the protein in the example above would only be considered 

 if the AOF peptone were derived from a recombinant process in which none of the ingredients in the broth used to make the peptone were directly derived from an animal.  

It is good that the precise AOF status of media components be understood and documented, and that there be a high level of transparency regarding manufacturing change for raw materials. It should be noted, however, there have been no indications that AO materials at the tertiary level constitute any safety hazard in cell culture–based pharmaceutical products. To provide anything above the secondary level of AOF requires a significant audit trail including reviews of bill of materials and various manufacturing steps, which are currently not specifically required by any regulatory agency. Currently, tertiary level AOF components are not being actively demanded by many manufacturers of biotherapeutics mainly because of how difficult it is to establish, control, monitor, and maintain supplies of such products. 

In addition, requiring tertiary level AOF media severely restricts the possible sources. As shown in Figure 1, one media supplier has made an effort over the past decade to qualify secondary AOF components, and in doing so, has made progress in achieving a higher level of AOF status for many components. Clearly, the higher biopharmaceutical manufacturers raise the bar for AOF status, the fewer components will qualify for use in their media.   

What Levels of AOF are Achievable? A Practical Example

Insulin is widely used in mammalian cell culture to delay apoptosis and thereby increase productivity. In the past 20 years, because methods of producing recombinant human insulin have come to the forefront, there has been a shift away from using bovine- or porcine-derived insulin.

  Recombinant insulin is generally a primary level AOF component. However, as worries about TSE and other animal-origin contaminants have increased, many biopharmaceutical companies have begun to ask media suppliers to consider producing secondary level AOF insulin, even though the therapeutic standard insulin that patients receive as an injectable remains primary level AOF.  

Cell culture media suppliers have responded by ensuring that the cell lines they use to produce insulin are cultured in AOF media. However, one of the greatest stumbling blocks to producing secondary level AOF insulin is at the step where pro-insulin is cleaved to produce active insulin (Figure 2). One of the enzymes used in the cleavage is trypsin, which is traditionally derived from bovine or porcine sources.   

Currently, one major insulin manufacturer is using a recombinant form of non-animal derived trypsin to produce a secondary level AOF insulin for bioprocess use. This secondary level AOF version is more expensive and less readily available than primary level AOF insulin. The India-based pharmaceutical company Biocon is developing a secondary level AOF insulin. Once it is available, biotherapeutics manufacturers will have another source for secondary AOF level insulin.  

If all the media components and enzymes used in processing insulin were derived from fermentations that use AOF components, this would produce tertiary level AOF insulin. In the future, insulin manufacturers may consider this option as a way to gain a competitive advantage. The perceived risk of contamination is still very low, however, so one might question whether continuing down this path to greater and greater levels of AOF status will provide sufficient benefits to justify the effort. 

Cell culture media manufacturers have three levels of quality control over the raw materials used in their media: basic analysis, questionnaires, and site audits. These levels are used because generally it is not feasible for media manufacturers to audit all of their raw material suppliers. Major media suppliers work with hundreds of raw material suppliers to source thousands of components and because each audit takes an average of two to three days and extensive travel, a team of full-time auditors would be required if every single supplier had to be audited.  

For well defined raw materials that form a very small proportion of the total volume of the media produced for clients, most cell culture media suppliers carry out a basic analysis. This analysis involves testing each raw material and comparing it against the Certificate of Analysis (CoA) provided by the raw material supplier. Such testing rarely reveals whether a product was made using AOF components, but if a product matches its written specifications, the testing can offer a degree of assurance that the vendor is selling what it says it is. Alternately, if the results do not match the CoA, the test will raise concerns and prompt the company to investigate. 

Cell culture media suppliers typically also ask their raw material manufacturers to fill out a questionnaire. The questionnaire should include questions such as:  

Is the material derived directly from an animal?

Does the manufacturing process use any other animal-derived components?

Does the supplier classify the manufacturing components and process as AOF?

What enzymes and cell culture media have been used to produce the raw material?

What cleaning and cleaning validation steps have been used to ensure there is no cross contamination of the product with any product of animal origin?

A questionnaire also can be used when a cell culture media supplier is unhappy with the results of a basic analysis. Having a raw material manufacturer provide additional documentary evidence that its component is AOF to either a primary or secondary level provides an additional level of assurance that the component is indeed AOF. 

Questionnaires have several disadvantages, however. Questionnaires take time to complete, and there is the potential for inaccuracy. Also, even if the information provided in response to a questionnaire is accurate, it is only a snapshot in time. Good communication with a raw material supplier and using a change notification system will serve to keep the information current and robust.  

For suppliers of large amounts of critical components of a cell culture medium (e.g., amino acids or insulin), a cell culture media manufacturer should conduct both a basic analysis and site audits to ensure that the written standard operating procedures (SOPs) are being followed by technical personnel. Many raw material suppliers follow current good manufacturing practices (cGMPs) and are ISO 9001:2000 certified; therefore SOP documentation should be readily available for inspection. A site audit is the best method of determining that a supplier of bulk raw materials really does understand its SOPs and is implementing them correctly for producing AOF materials. The audit should review batch ingredients and supporting documentation that confirms the origin of those ingredients. 

In addition, a site visit provides the opportunity to ask the technical personnel in-depth questions. A direct interview reveals more than having staff send in answers to a questionnaire, which can sometimes be completed by a committee or someone other than the person in charge of process handling. Media manufacturers, just like the FDA, may use the track record of a supplier to determine the frequency of audits. This allows the media manufacturer to balance its resources against risks.  

Biopharmaceutical companies are concerned about the potential for cross contamination between AOF and non-AOF manufacturing processes carried out in the same facilities. To address this concern, some modify their definition of AOF to require that AOF products be made in an area where only AOF production is performed. For many cell culture media suppliers, however, such separation is not always possible to achieve and many AOF products or raw materials are still manufactured alongside those of animal origin. To overcome this challenge, many media suppliers carry out validated cleaning and process controls to ensure there is no potential for animal product carryover, and provide information to their customers about these steps. 

Many manufacturers of good quality, cGMP-grade raw materials are now located around the world, including countries with emerging suppliers of media component raw materials like China and India. Components sourced from those countries are being used more frequently, especially by companies that are seeking to keep costs down while improving the level of AOF status. Other companies, however, prefer not to source from such countries. Mandating limitations on the countries from which raw materials can be imported, or requiring that all raw material suppliers be audited, however, can increase manufacturing costs. Those costs may have to be passed on in the price of the media and could mean the finished product would become prohibitively expensive.  

When choosing a supplier of AOF cell culture media, there are a few important question to ask. For example, does the supplier have a secondary source of critical components that is equivalent to the primary source? And what steps has this supplier taken to mitigate AOF risk and the risk for back order? Many cell culture media manufacturers do not maintain large inventories of raw materials, and instead carry just enough to cover one to two months without any new deliveries of critical components. This reinforces several important recommendations about maintaining any supply chain:  

Attempt to forecast as accurately as possible, so that suppliers are not surprised by sudden increases in demand.

Use a mitigating safety stock strategy to assist with sudden, unforecasted increases in demand. 

Avoid including specifics in regulatory filings that will leave suppliers without options to use alternative equipment or locations to make media. For example, do not indicate the serial number of a piece of equipment used to make media.

Set specifications for the desired quality and put the burden of compliance on the media supplier (which can be audited as frequently as requested). 

Work closely with media suppliers to ensure product specifications balance risks with cost and availability.

The lack of industry standards around the definition of when the manufacturing process begins and ends, as well as whether an adventitious agent can remain through various AOF levels, will continue to affect perceptions of safety and patient risk. This is why the levels of AOF necessary must be considered when choosing a cell culture media supplier. If most therapeutics are only primary level AOF, then is the additional burden of evaluating secondary or tertiary level AOF components really essential? Biopharmaceutical companies that demand cost-effective, guaranteed AOF media and ingredients should determine how well their cell culture media supplier is assessing their raw material manufacturers before entering into a long term agreement. 

In short, biopharmaceutical manufacturers must ensure public trust that they are maintaining the highest levels of safety for their end products. It is important to weigh actual risk when requiring levels of AOF beyond the primary level. If a critical or high-cost AOF component such as insulin is going to be used, the biopharmaceutical company is justified in specifying the assurances it needs to be confident it is getting the safety required. Following the steps a media manufacturer uses to qualify raw materials and working with the company to agree on the acceptable level of risk versus benefit (for example, willingness to accept an audited source from India that meets GMP requirements and an AOF definition at the desired level to ensure a regular supply) should help achieve desired patient safety while ensuring cost-effective availability. 

 is the director of cell culture product development, 

is a senior product manager, all at Invitrogen, part of Life Technologies Corporation, Grand Island, NY, 716.774.6860, 

How to successfully balance patient safety with supply-chain management

Strategies for Sourcing Animal-Origin Free Cell Culture Media Components

Technology transfer is a complex technical process that does not often receive the resources or considerations that it needs to ensure success of complex manufacturing processes. Ideally, technology transfer should be managed by a dedicated division or specialist group, which is one of the benefits gained by outsourcing manufacturing projects to an established contract manufacturing organization (CMO). A dedicated team knows that technology transfer programs are not always straightforward, quick, or easy to perform and that there will always be challenges to overcome and problems to resolve to achieve success. Their experience will also have taught them that clients often have very little idea as to what the transfer process involves, which means that the development of a trusting relationship between the client and the CMO is essential. 

At many stages during biopharmaceutical product development, it will be necessary to transfer processes from one place to another. Whether this is internally between teams within a company (for example, from the process development team to the scale-up or manufacturing team) or externally, from one company to another, the key objective is to execute the transfer with minimal disruption or unnecessary cost. This can be an overwhelming proposition for small- to medium-sized start up companies (usually with an academic or research background). These companies will prefer to transfer early-stage processes to a CMO for the first time-for scale-up and manufacture of Phase ½ clinical trial materials-and have limited experience of scale-up or the regulations and expectations surrounding a current good manufacturing practices (cGMP) process. Poor planning, unclear documentation, and bad communication all can lead to an inefficient transfer program, and more often than not will lead to the receiving team having to develop parts of the process that have already been established. Any inefficiency in the technology transfer program will inevitably result in delays in production, with the related theoretical loss in revenue and additional increases in the cost of the transfer. It is therefore essential to put serious time and resources into the planning stage of a technology transfer program.

	There are no fool-proof strategies that can guarantee a smooth technology transfer, but certain factors have a large influence on success: meticulous planning, technical understanding of the manufacturing processes, and good communication. A strong emphasis need be placed on a risk-based approach. This involves the identification of risks, both technical and scientific, and logistical, at an early stage, to develop avoidance or mitigation strategies far enough in advance to help keep the transfer program on course. This kind of strategy relies on a highly knowledgeable team of people who have the necessary experience to be able to anticipate the issues that may arise, and excellent communication between the sending and receiving units.

	For a CMO, one of the biggest challenges in technology transfer can be dealing with client expectations. For first-timers, the idea of technology transfer can seem quite simple and straightforward: "We've developed this process at our facility-how hard can it be to do the same thing in a new place?" The truth is that even transferring the simplest process will be a complex progression of planning, testing, and optimizing, especially considering that most biotech products being transferred to a CMO will be moving into clinical trials with the intention to eventually manufacture commercially. This should mean that processes are, at this stage, being looked at critically to assess suitability for scale-up and regulatory compliance. Clear communication and the development of a good relationship between both parties is clearly of benefit to all from the very start of the project.

	A risk-based approach not only maps out potential issues and allows contingency plans to be put in place, but it also facilitates communication between the sending and receiving parties. The approach allows a sturdy but flexible framework, which provides structure to the technology transfer program. Having such a systematic and forward-looking procedure can help during the initial stages of the program when readjustments of expectations (with regard to time and cost) are taking place, and also establishes a climate that is pragmatic and professional, leading to an increased level of success.

	A risk-based approach involves asking a lot of questions before the event, rather than after it. Before a technology transfer program even gets off the ground, the following questions must be addressed:

		Does the process fit in the receiving facility and its established platform?

		Are the requirements for the material and timelines realistic?

		Are any long lead times required to run the process? (Raw materials, equipment, and consumables can play a major factor in causing long lead times. For example, differences in raw materials can produce product characteristics that do not fit the specification of the sending unit. New suppliers may cause delays and add costs.)

		Is the process scaleable and robust? Has it been shown to perform acceptably over tested ranges during development?

	The answers to these questions help to ascertain the suitability of the CMO as a good partner for the manufacture of that particular product, and also highlight the need for process development to prepare the product for scale-up.

	Common technical issues that arise during a transfer program involve the technical understanding of the process: are all the parameters used in the process fully understood, and what happens if the exact parameters cannot be duplicated? Challenges also arise involving the understanding of which parameters are critical and which are not. All of the necessary information to address these challenges can come directly from previous data recorded by the sending unit-but only if documentation is clear, and a culture of open communication has been developed. It is very important to see all of the data, especially the data from development runs when the process may not have worked optimally, so a full picture of the range of parameters can be developed and better understood. Other issues involve understanding the operational windows for the process, in other words, understanding how the product behaves during the process so that operations can be run on successive days. Therefore, it is very useful to have in-process stability data transferred before the technology transfer begins.

	Understanding equipment differences between the CMO's equipment and that used at the sending unit's site is also very important. No two sets of equipment operate and perform in exactly the same way, or to the same level of tolerance. Just because a piece of equipment can report a certain value to a number of decimal places, it does not follow that the value shown is accurate to those decimal places. Therefore, if critical parameters are set around a specific piece of equipment, it is very important to understand the tolerance and accuracy that the equipment has been calibrated to report to.

	Logistical issues to consider can be as obvious as the time it takes to order and receive consumable supplies and ingredients, but if these factors are overlooked, it could result in an unscheduled halt in production for days, or even weeks, which would play havoc with timelines and budgets.

	The approach taken at Cobra Biomanufacturing is outlined in Figure 1 and consists of an initial evaluation of the program against the business model and scientific expertise and technical fit. At this stage, the strategy and approach to the program would be developed and defined. Information regarding the process would be transferred and communicated by technical visits to the client's facility to observe the process in operation and through documented information transfer. The outcome of this stage is an assessment of the process for transfer and whether or not additional development activities, equipment, or approaches are required to transfer the process. If additional work is required, it is done before any transfer run is performed. Historical data generated from early development and defined process runs performed at the client site is then used to set the acceptance criteria for the transfer runs. Agreement for the criteria is achieved through communication and meetings with both parties. Transfer runs are then performed (which can include technical staff from the client's site) at the receiving site, to the defined scope. The success of the transfer run is assessed through measurement against the predefined criteria. The final stage of the initial technology transfer is a report and review process where all operational, technical, and scientific information is assessed for the program's progression. It is necessary and essential that all stages of this process require communication, collaboration, and team work between the sending and receiving parties.

	A lot of clients expect that their process is ready to transfer directly into a CMO and can be run straight away. This always leads to issues if the middle steps are ignored, or performed inefficiently. Transfer into a CMO should not be looked on as a quick and cheap option-the cost for additional development works to ensure the process is in compliance and technical equipment fits in the CMO facility should be discussed at an early stage.

	It may appear that the need for good communication has been over emphasized in this article, but the truth is that it can't be emphasized enough. And it's not just clear communication that is essential-it is just as important that an atmosphere of open, two-way sharing is fostered between the sending and receiving unit. It is not unusual for sending parties to be nervous about sharing all the data related to their product, especially if there is negative data, but once confidentiality agreements are in place, there should be no need for hesitation. Holding back information can invite unforeseen challenges further down the line.

	As with any outsourced contract project, success is always more easily achieved when both client and contractor pull together to achieve a common goal. This is never truer than with technology transfer. A collaborative team approach accomplishes a number of key objectives that help to drive the success of a project. These include:

: multiple contacts from both parties working together as a team ensure that strong relationships are built across multiple departments in the companies involved.

: by working with multiple contacts rather than single points of contact in each company, there is less chance that important information will be overlooked, and there will be more direct contact between the people asking the questions and the people who know the answers.

: working together makes the project a team effort with the sending unit often working side by side with the receiving unit to resolve issues and tackle challenges. This helps to avoid the adoption of a blame culture-something that would always be detrimental to team morale and the process as a whole.

	It is important to understand that the technology transfer process will involve almost every function in a CMO, not just the dedicated technology transfer team. It is, therefore, important that the culture of open, transparent communication is not limited to the technology transfer function, but is indicative of the overall corporate culture in that organization.

	As with everything, the devil is in the details-transferring the exact procedure for an operational step is extremely important. If critical information is not included in the documentation or the transferred information (verbal or other), then the receiving unit (CMO) does not know that it is important or needs to be done.

	For example, it might be that the CMO usually autoclaves media for fermentation processes to sterilize it for use. This can be fine in the majority of cases. However, if the client has only used filtered media, or knows that autoclaving may be detrimental to the media, then this is important information to pass on. Time, cost, and resources can and have been wasted performing large-scale fermentations that resulted in poor cell growth because the media was prepared in a manner detrimental for the growth of a specific cell type. Clients must not assume that just because they perform a relatively straightforward and basic operation a certain way, the CMO will perform that operation in the same way. This is not carelessness or incompetence on the part of the CMO, it is just that not all basic operations are performed the same way everywhere. This example may seem obvious but it is fair to say that in 90% of technology transfer cases, it is the small, seemly insignificant details that are overlooked, which in turn results in delays or failures of the transfer.

	No CMO will run 100% perfect technology transfer programs 100% of the time. There will always be challenges to learn from, and so it is essential that the CMO has some kind of feedback and review process in place. For example, at Cobra Biomanufacturing, the technology transfer team has full visibility of all programs in development and cGMP manufacture, as well as those in technology transfer and scale-up. The team develops and refines its approach through contract-specific review meetings at key stages of the program. All areas involved in the overall program are represented, irrespective of the stage at which the contract is. For example, a development stage is reviewed by the manufacturing, testing, and quality staff-so that there is continuity for the program and feedback and learning from all functions. Operating an integrated approach with teams consisting of cross-functional staff for each stage also maintains and fosters a climate for continual improvement, both in a specific program and also across programs.

	Technology transfer is unavoidable if you intend to develop a biopharmaceutical from initial identification through to clinical trial and on to market. A successful technology transfer program must have a strong basis in clear and open communication with all parties, and the development of a relationship built on trust. A strategic and scientific risk-based approach facilitates clear communication between both parties involved in the technology transfer, and ultimately raises concerns and questions at an early stage, enabling avoidance or mitigation strategies to be developed far enough in advance to promote the smooth running of the transfer program. This kind of approach helps to foster and develop a climate that is pragmatic and professional and will help match the expectations of both parties and lead to an increased level of success.

 is the head of technology transfer at Cobra Biomanufacturing Plc., Keele, UK, +44 (0) 1782 714181, 

Effective tech transfer can save time and effort in later manufacturing processes.

Handling a Risky Business: How to Ensure Successful Technology Transfer

Many drug manufacturers may not have the capability to perform all manufacturing operations at their own establishments for economic reasons. Others opt for subcontracting their operations. Outsourcing introduces considerable complexity into ensuring compliance with good manufacturing practices. This article offers FDA guidance for how to ensure compliance in the outsourcing environment.

Historically, the manufacture of biological products in the United States involved a limited number of firms that were responsible for all the steps in the process including drug development, testing, labeling, packaging, and distribution to the markets. Since then, an increase in the demand for new products, along with market pressure for innovation, has fostered the growth of specialized firms and subsequent outsourcing. 

According to CDER's guidance for industry, 

Quality Systems Approach to Pharmaceutical CGMP Regulations

, outsourcing involves hiring a second party under a contract to perform the operational processes that are part of a manufacturer's inherent responsibilities.

  For biological products, outsourcing refers to the delegation of manufacturing responsibilities to different types of cooperative arrangements—from the license applicant to a contractor. These arrangements share a common economic goal—bringing products to market more quickly at reduced costs. The FDA's guidance to industry, 

Cooperative Manufacturing Arrangements for Licensed Biologics

, describes different types of manufacturing arrangements for outsourcing.

  Cooperative arrangements recognized by the FDA include: a) a license holder obtaining a short supply product from other than the licensed facilities (see 21 

 601.22 for more details); b) two or more licensed firms sharing manufacturing through each firm's individual responsibility for specific aspects of the manufacture of a product with neither being licensed for all aspects of the manufacture; and c) firms performing all or some of the product manufacture as a service to the license holder. Regardless of the type of cooperative manufacturing arrangement, all firms involved in the outsourcing of a manufacturing process must be in compliance with the FDA regulations. 

According to the FDA's regulations, the manufacturer is legally responsible for the manufacture of a biological product. Both license holders and contractors fall under this definition because they take part in the manufacture of the biological product. License holders and contractors have responsibilities under the law (see the PHS Act, 21 

 Parts 210, 211, 600 through 680, and 820 for more details). 

The license holder ensures compliance with product and establishment standards through the implementation of current good manufacturing practices (cGMPs). The contractor maintains effective and timely communication with the license holder. Contractors must inform license holders of all deviations in manufacturing methods, adverse events, tests and investigations possibly affecting the product, proposed changes in manufacturing, and any changes in the facilities.  

Without exception, all outsourcing participants must comply with FDA regulations. Failure to comply with cGMPs or to fulfill license requirements may justify compliance action. Details for complying with cGMPS can be found in the Food, Drug, and Cosmetic Act (21 USC 301) and the 

Outsourcing Brings Complexity to the FDA and Industry

Outsourcing introduces considerable complexity into ensuring compliance with cGMPs. Outsourcing can result in having multiple contractors involved in the manufacture of a single compound. Today, it is not uncommon for a biological product manufacturing process to include more than 10 participant sites. This increase in participants translates into a commensurate increase in FDA inspections.   

Inspections have been expanding to include ex-US firms as manufacturers seek to reduce costs. This has resulted in an explosion of travel time and expenses for inspection. Foreign manufacturing site inspections necessitate obtaining country-specific clearances, multilingual staff to manage and control documentation, and increased interaction by the FDA inspection staff with a variety of international business cultures.   

In their interactions with foreign manufacturing sites, the FDA inspectors encounter different local regulatory requirements and compliance expectations. These interactions also may entail translations of standard operating procedures (SOPs) into multiple languages. The need to conduct foreign inspections of manufacturing sites has led to an increased dependence on information technology and reliance on electronic meetings with new communication modalities for  more effective communication. 

Furthermore, interactions with more firms also translate into more reviews and inspections of manufacturing support sites. These sites include laboratories, suppliers, labelers, storage sites, and packagers in and outside the US. Warehouses for unlabeled products also may be inspected. (Warehouses for finished labeled and packaged material usually are not inspected unless problems with the storage conditions exist.)  

The complexities faced by the FDA translate into complications for the manufacturing firms. Each addition of a contract manufacturer means another supplement to an existing biological license application. Additional inspections may be needed for these submissions, depending on the manufacturing process or testing being contracted. For example, a contracted bulk manufacturer or a filling manufacturer normally requires a prior approval supplement and a release testing laboratory generally requires a change-to-be-effected in 30 days supplement.  

The FDA encourages manufacturers to submit thorough and comprehensive submissions. To expedite the process, drug manufacturers must follow the FDA regulations and guidelines as closely as possible. These guidelines are the basis for reviewing submissions and are the documents most familiar to the FDA reviewers. Editing and organizing the material presented to the FDA in a coherent document can pay huge dividends for the applicant. Effective communication facilitates understanding of the material presented and saves review time. Using a table of contents and a list of acronyms minimizes misunderstandings. Furthermore, providing background information with each submission clarifies the product's history and the company's future plans. Poor submissions, like poor manufacturing compliance history, can slow the review and approval process of submissions. 

Regular and timely communication with the regulatory project managers 

The FDA encourages communication with the agency. Different avenues are available to manufacturing firms to accomplish this. For example, alerting the regulatory project manager (RPM) responsible for a submission of any correspondence and amendments being sent to the agency can be very useful both to the firm and to the FDA. This builds trust and enables both parties—the RPM and applicant—to keep abreast of progress with each submission. 

The FDA encourages meetings because carefully planned and well-run meetings facilitate understanding of the material being presented to the agency. Teleconferencing is an option when a face-to-face meeting is not possible. Meetings facilitate a mutual understanding of each party's needs. 

Taking the time to understand how new regulations can affect manufacturing operations, and asking the FDA questions as needed can help the company. Also, gaining an understanding of the regulations and guidelines can save time, money, and resources. 

Visit the FDA web site and keep informed 

The agency believes in clear and timely communication. The FDA's web site is therefore constantly updated with the most current information available to the public. There are options to e-mail questions and to provide comments on regulatory policies.  

One of the most common mistakes made by firms is not having their submission edited by a single source. Reviewers often read  submissions containing sections written by different authors that do not agree among themselves. The sections sometimes are incomplete or even contradictory. This is not only confusing for the FDA reviewers, but also wastes precious review time. Such a lack of commitment in creating a quality submission could raise questions about the company's commitment to quality in general.  

Limit information to what is being requested 

Manufacturing firms should be aware that providing more information than what is requested maybe unnecessary. More information takes more review time and does not necessarily improve the quality of the information in the submission.  

Learn from others' successes and failures  

Firms need to be proactive and informed. The agency's web site gives access to current problems confronted by the FDA. News about FDA actions is also available through various media outlets including professional journals. Firms must learn from examining how the agency confronts emerging issues. 

Be sure to provide complete information about your facilities, including but not limited to the FDA establishment identifier number, correct street address of the actual manufacturing plant, the name and number of a contact person at each plant, and the exact function of the facility in the context of the drug application. All facilities should be submitted in one section of the application, so that they are easy to locate for the reviewer. Also, a quick response to the agency's queries can reduce guessing time spent on a submission and earn quick feedback from the FDA.  

Cooperation is also key. Good team players help each other accomplish their goals by respectfully listening to each other's point of view and without taking antagonistic positions. Working together accelerates review and ensures approvals of qualified products on time. 

Finally, the FDA recommends having written agreements with contractors that identify: 1) the locations to be used for manufacture; 2) the responsibilities of each participant; 3) the specific product shipped to the contract facility; 4) the manner and conditions of shipment; 5) product segregation SOPs; 6) a commitment to inform the license holder of errors and deviations; and 7) how and when the contract facility will be audited. Regulatory actions with legal consequences can be easily avoided with a well-written agreement.   

One of the FDA's goals is to facilitate product development and manufacturing flexibility, and therefore, it supports advancement of new and innovative ways that will lower the cost of drug development while advancing the critical path for a drug product's review. Providing guidance to manufacturing firms on different types of outsourcing and recommending how to improve their submissions is one more way the FDA shows support for this goal.   

This article was written by Marlene Garcia Swider in her private capacity. No official support or endorsement by the Food and Drug Administration is intended or should be inferred.  

is a regulatory project manager in the division of gastroenterology products at CDER, FDA, Silver Spring, MD, 301.796.2104, 

 1. US Food and Drug Administration. Guidance for Industry. Quality systems approach to pharmaceutical CGMP regulations. Rockville, MD; 2006 Sept. Available from: 

 2. US Food and Drug Administration. Guidance for Industry. Cooperative manufacturing arrangements for licensed biologics/ Rockville, MD; 2008 Nov. Available from: 

Outsourcing introduces considerable complexity into ensuring compliance with good manufacturing practices. This article offers FDA guidance for how to ensure compliance in the outsourcing environment.

FDA's Recommendations to Industry Regarding Outsourcing

The contract analytical laboratory (CAL) plays such a key role in the support of its clients that the quality of communication between the CAL and client is arguably just as important as the quality of the science in supporting the production of biopharmaceuticals. Communication is just as important when out-of-specification (OOS) results arise. It is always to the manufacturer's advantage if the CAL has the resources, back-up, and communication channels available to provide an assured service when results are OOS.

For any biotech company considering using a contract analytical laboratory (CAL) to support its product development or manufacturing, the science on offer must be of the highest standard; the laboratory must be competent to carry out all of the analytical procedures required.  

Analytical competence, however, is only one part of the story. Communication is extremely important in supporting the production of high-quality biopharmaceuticals. This is especially true when the results of an analysis indicate a problem with the product, as in the case of out-of-specification (OOS) results. 

Having identified a suitable partner laboratory, the first point of communication between the manufacturer and the CAL should be with the latter's quality assurance unit. This will be to ascertain the quality standards in operation, to receive copies of the letters of approval from the MHRA or the FDA, and to view at first hand the laboratory's facilities, not just for carrying out analysis, but also, for example, for receiving, storing, and disposing samples. 

Assuming the CAL has the necessary quality systems in place, the discussions should focus on agreeing on the contents of a confidentiality agreement and technical agreement. The CAL is likely to have many other clients, so the manufacturer may wish to establish how potentially sensitive information will be protected from other companies' auditors. Confidentiality agreements may be prepared by the manufacturer or by the CAL, but in either case, must be agreed on by each party.  

In Europe, EU Directive 2003/94/EC (the so-called "Orange Guide") makes it clear that a written contract is needed to define duties and obligations between the parties for good manufacturing practice (GMP) analysis. It is arguably impossible for a contract to cover every eventuality, but the more detailed the contract, the better. Nonetheless, the inspection authorities in the UK have noted, for example, that the contract should not only indicate that the laboratory will inform the client of OOS results, but also state how and when the results should be notified. Similarly, the contract would not only state that samples should be disposed of,  retained, or returned, but also would specify how and within what period of time.  

Either party may prepare the technical agreement. A CAL-prepared agreement often takes a generic approach to analytical testing, whereas manufacturer-prepared agreements are more likely to be written to cover specific analyses on specific products.  

Regardless of authorship, both parties must check the contents of any agreement closely, because not all demands that are sensible in theory are actionable in practice. For example, the manufacturer may ask for the destruction or return of all documents, records, and data that belong to them. However, with the dependence of the modern laboratory on IT systems that are backed up every day, the destruction (i.e., deletion) of electronic records is a nearly impossible task. Understanding and accepting the requirements and limitations of both partners from the outset is critical for maintaining a good working relationship in the long run. 

Although contracts form the structure of the communication, and the legal basis for carrying out work and resolving disputes, true communication is a two-way activity. Both sides should feel comfortable requesting information from each other. The client can help the CAL by sending as many details as possible with the sample to be analyzed. Safety data sheets should be sent where appropriate, with details of the testing requirements and disposal instructions. From the laboratory's perspective, it is always better to receive too much information rather than too little, yet it is surprising how often clients appear comfortable sending samples with the simple, but inadequate, instruction "for testing." 

That said, the CAL should be flexible and ready to receive sample information in electronic or paper format. Many CALs can copy data from a spreadsheet into a laboratory information management system (LIMS), or have a standard sample submission form available. When such a form has been designed by the CAL, it can be expected to request all the details the CAL needs. If the CAL does not have a form, then it should be suggested that it creates one.  

Good communication is most important on the few occasions when an analysis does not progress as planned. These occasions can be broadly divided into two main categories: a deviation from the agreed methodology or an OOS result.  

The technical agreement often will reference the methodology and procedures to be followed for the requested analysis. Hence, a deviation is defined as "a departure from an approved instruction or established method." The CAL should have a "deviations" standard operating procedure (SOP) to be followed in such circumstances.  

However, deviations from methodology must be accepted and approved by the customer before starting the analysis. The laboratory must discuss the deviation with the client and provide evidence to validate that the deviation is appropriate. Such deviations should be detailed on the test report. 

If the deviation is to a customer method, and is to become permanent, then a change control process needs to be instigated. The change control process should also be documented in an SOP. The change can then be validated by submitting analytical data to the client with a copy of the draft new method for after review, the client must provide documented approval that the change provides an improvement to the method.  

Whenever results are OOS or out-of-trend, a formal investigation must be undertaken. The investigation invariably starts with a thorough review of the raw data. Assuming no errors are noted, then the CAL should contact the client to discuss the next course of action.  

It may be that no further action is required. Clients may occasionally (and without notice to the CAL) request the analysis of known OOS samples to test the competency of the CAL, or to confirm an in-house result. Clearly in these two cases, the OOS result is to be expected.  

However, when the OOS is unexpected, further investigations will be required. 

The FDA's most recent guidance on investigating OOS test results provides some significant additions to previous guidance.

  Its most significant changes from previous guidance are the following;   

the scope and background was revised to clarify the applicability of the document 

the section on investigating OOS results, averaging, and concluding the investigation was reorganized

specific guidance on certain issues was added or clarified.

The guidance addresses investigations of OOS results in the laboratory phase, including responsibilities of the analyst and supervisor, and when indicated, the expansion of an investigation outside of the laboratory to include production processes and raw material, as appropriate.  

The new guidance is a bit confusing in certain parts, however, and from the perspective of the CAL, there are one or two surprising omissions. In the FDA guidance, an OOS result is defined as,  

 "all test results that fall outside the specifications or acceptance criteria established in new drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications."

 Interestingly, Section II of the FDA guidance states, "The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm." Later, in Section III it is stated, "For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm's quality control unit (QCU), who should then initiate the full-scale OOS investigation."

These two statements appear to contradict each other, suggesting on the one hand that the CAL has equal responsibility with the manufacturer, and on the other that it is only responsible to the manufacturer. In practice, of course, investigating OOS results is usually a mutual decision, prompted by the reporting of results by the CAL, proposal of follow-up investigation by one or both parties, and agreement of the contractual basis on which the work is being carried out. 

The new guidance is surprisingly lacking in detail as to how OOS results should be classified and followed up. It merely notes that, "the source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process." 

From the laboratory's perspective, it is far more useful to drill down to the detail and assign the error more specifically (e.g., dilution error or wrong sample weight used). Our own laboratories would always seek to assign a conclusion to any investigation (i.e., calculation error, method error, equipment error, technician fault, or genuine OOS). This affords the opportunity to analyze OOS results for specific trends to highlight potential weaknesses in our own quality system, and also provides greater assurance to the client that an OOS result reported as arising from manufacturing error is indeed genuine. 

Section III of the guidance states that, "corrective action to prevent recurrence" should occur whenever laboratory error is identified as being the cause of an OOS result. However, this author is in favor of the term "preventive action," which is used later in the section.  

Leaving aside the semantics, where the laboratory has shown that there has been a fault in the production process rather than the testing process, there is more investigative analysis that the laboratory can undertake to establish the root cause of the OOS result.  

It helps if there has been a history of good communication between the CAL and client. Investigating an OOS result may necessitate the client disclosing sensitive, proprietary information to the CAL so that they can make sense of what has gone wrong. It may be necessary to open up manufacturing facilities to the CAL so that samples can be taken and processes be understood.   

Whoever does the investigation, it is always clear that the OOS result must be taken seriously, and acted on. Testing into compliance is both unscientific and objectionable. The guidance notes make it clear that when there are no laboratory or calculation errors identified and there is no scientific basis for invalidating the initial OOS results in favor of acceptable retest results, then, "all test results, both passing and suspect, should be reported."  

It goes on to say, "It is critical that the laboratory provides all individual results for evaluation" as "averaging the result(s) of the original test that promoted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate." This practice "hides variability," according to the guidance and which goes on to say that, "relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specification." Anyone familiar with the USA versus Barr Laboratories case of 1993 will recognize the importance of not ignoring OOS results, and why testing into compliance is unacceptable.

Whether out of specification, or more usually, in specification, one of the most important pieces of communication between the CAL and client is the actual result of any analysis. Modern LIMS allow for the production of secure, electronic copies of certificates of analysis (CoA), which permit the CoA to be e-mailed directly to the client's inbox, rather than relying on the slower postal service. In some cases, the laboratory may be able to grant the contract-giver access to secure parts of its IT infrastructure or LIMS for live results. The client can view the progress of the analysis from sample receipt through to the final result.  

If this is the case, and if appropriate, then the requirements of 21 

 Part 11 should be obeyed, with the appropriate use of automatic password ageing, unique identifiers, limiting access, and audit trials. The complexities of 21 

 Part 11 are such that no further detail can be entered in here. 

The raw data, copies of the CoA, and all associated correspondence can now be archived for the period agreed in the technical agreement.  

Communication between contract analytical laboratory and client is extremley important when out-of-specification (OOS) results arise.

BioPharm International-04-02-2009

Batch Release Testing: A Geographical Driver For Outsourcing in Europe

Strategies for Sourcing Animal-Origin Free Cell Culture Media Components

Handling a Risky Business: How to Ensure Successful Technology Transfer

FDA's Recommendations to Industry Regarding Outsourcing

Benefits of Effective Communication with a Contract Analytical Laboratory