Responsibility in a contractual agreement between two pharmaceutical companies has been indicated as one of the common cGMP (current Good Manufacturing Practices) compliance challenges during this last decade. Yet, the real challenge is much broader and usually more basic than cGMP compliance. This challenge is raised to a high level of risk when selecting and developing collaboration for manufacturing a sterile pharmaceutical product.
Whether you are selecting a CMO (Contract Manufacturing Organization) for sterile manufacturing of your product, or if you are a CMO seeking clients, this is part of a critical business activity that requires good planning, good understanding of the criteria, and a consistent robust approach to making such a selection. It is often the case that a client has product knowledge and a CMO has process knowledge, which can lead to an open sharing of each other’s knowledge and the building of a total knowledge ‘design’ in the collaboration.
“Both the manufacturer and contractor share responsibility for product quality; however, the manufacturer remains ultimately responsible” [1]. We all agree that this is a foundational risk for all CMO partnerships. Yet, this is not alone sufficient for building a relationship. The following, current thinking has been repeated many times in response to inspectional findings and ‘Warning Letters’ when compliance issues arise: adequate compliance is one of the two key reasons for developing a successful relationship. The other reason is good business for sustainability. It is important to understand that all relationships have a cycle of development, from leadership to team skills and communication skills.
Shown in Figure 1 is a diagram that provides a general perspective of the different stages of development (that originated from training for team building) [2]. When beginning a partnership with a CMO, expect to move from the early stage, ‘forming’, through the other cyclic stages: ‘storming’, ‘norming’, ‘performing’ and then recycling when something changes within the relationship. For example, changes in leadership, new technical oversight, revision to compliance perspective, or manufacturing scale can impact and cause cycling to an earlier stage.
Robust partnerships in the pharmaceutical and biopharmaceutical business are keys to the sustainability of long term productivity. Beneficial partnerships can occur with many different supply chain contributors: for example, manufacturers of excipients, components, or active ingredients, finish-fill processes, and storage/distribution facilities.
Figure 1. Stages of Development of a Partnership
This article will discuss the general considerations of selecting a partner, designing the relationship and building robustness and quality. The examples used are for learning purposes and are not all inclusive.
Third Party Relationships
First, one must understand that there are direct and indirect costs and benefits to every business activity. It is important to know what these are.
Some examples of direct costs are those associated with production scale and equipment, time, and re-production. Indirect costs include customer relationship management. Some examples of benefits are production efficiency, technical capability, and increased capacity. Indirect benefits include access to more experienced personnel and coveted scheduled slots. The perspectives of a team comprised of manufacturing, microbiology, quality assurance and regulatory scientists are crucial in the selection process, although individual perspectives may be more appropriate at designated stages of the process. For example, during an early clinical phase, a formulation development scientist would be beneficial; for aseptic fill/finish operations a scientist with expertise in aseptic technology is a smart choice; and for transfer to a CMO for commercial production, scientists familiar with technology transfer can add important perspective to the team.
One can learn from every relationship that there are costs and benefits. The balance between these is crucial input for decision-making success.
How do we define partnership?
It is unique for each company. Some key words/phrases can emphasize how this definition develops: agreement, collaboration, relationship, cooperation, connection, partners, union, association, teammates, together, one leads one follows, consensual, equivalent ownership and responsibility. Webster [3] defines ‘partnership’ as:
- “A state of being a partner; participation” and
- “A relationship resembling a legal partnership and usually involving close cooperation between parties having specified and joint rights and responsibilities”
A very relevant description of partnership is, “The most effective relationship is a true collaboration where two partners interact with transparent communication. The relationship works best when both sides view it as a mutually beneficial alliance” [4].
Remember, even though responsibilities are shared, each client of a partnership has objectives and meeting those objectives must be aligned with agreeable terms and actions on how to meet the objectives.
Another perspective that fits well with the important aspect of culture and values of an organization was stated by Steve Jobs, former CEO of Apple: “One way to drive fear out of a relationship is to realize that your partner’s values are the same as yours; that what you care about is exactly what they care about” [5].
Seeking for and realizing that your partner’s values are the same as yours is the best way to raise the relationship to another level, the trust and confidence for a successful partnership.
Why Outsource?
Before a model can be designed, the reason for outsourcing must be defined. For each reason, the business model may differ or be modified to fit the purpose.
Some common and current reasons for outsourcing in our industry are:
- Organization lean approach outsource routine manufacturing ·· outsource ‘complex’ or ‘specialized’ manufacturing (biopharm versus classical drugs)
- Cost savings – outsource non-manufacturing activities (e.g., lab)
- Overflow capacity – outsource overflow
- Access to unique product and/or process
A simple way of learning about the criteria for selecting an outsourcing partner is by understanding the “5 Cs of outsourcing” [6]. Each area requires requisite review and determination of where a potential CMO fits.
Outsourcing Criteria—5 Cs of Outsourcing
- Credibility
- Culture
- Capability
- Capacity
- Cost
The meaning of each criterion is critical in your selection process. Costs/benefits were mentioned earlier, and the realization that each of these criteria can lead to either increased cost or increased benefit, or both, are important to take into consideration.
Another key cost factor is that any CMO you consider should be able to demonstrate to you that it has independent financial standing. Without this financial strength, any partnership can fail. For example, be cautious if your company’s business makes up a large percentage of a CMO’s business. Your company’s business cycles are affected by many different factors, and you do not want a delay in your programs that might put a partner at a risk of going out of business. Weigh the cost/benefits when choosing between a CMO that performs sterile operations as their primary business as compared to a CMO that has multiple operations (possible sterile and non-sterile manufacturing) and may not stress or indicate to you the importance of consistently adequate resources and facility/equipment maintenance for the sterile operations, in particular.
Your Business Model
A business working model is based on roles and responsibilities, culture and values. The third party model should be designed for agility so that it can be changed as experience and learning develop. The business model is how business is accomplished. Your business should already have this model in mind or in practice, before any third party relationship is conceived.
The following are points to consider when developing a good business model for the partnership. Also, you might notice that some organization charts are a simple way of showing a business model.
- Who is the lead decision-maker, or is it shared and consensual? Who makes the quality decisions? Who makes the decisions on costs?
- Who is the main contact for communications, and how will this process work?
- Are quality and ethics the most important parts of the organization values?
- Is maintaining IP (intellectual property) protection considered?
- How important is regulatory compliance?
- What drives decisions in the manufacturing process, e.g., cost, or quality?
These parameters are built into the business model. How clear and defined is the organizational structure around quality, compliance and cost issues?
Purpose, Scope and Key Roles
Once we take the business model, a very high level, as the overriding map for the CMO relationship, then we get down to more detail to determine what criteria are significant enough to provide us with information about a CMO for our selection.
These criteria are based on an intent and scope of the CMO selection. Therefore, for sterile manufacturing, one should develop a statement of purpose/or intent and the scope.
For instance, an example of intent for R&D: consistently manufacturing 10 clinical batches of sterile XXX for injection using aseptic processing and sterilization technology and meeting compliance of global regulations (FDA, MHRA, JFDA, MPA).
And, an example of scope: clinical batches will be manufactured at commercial scale with potential for future commercial scale-up when product is approved.
Aligning with the purpose and scope, the model comes into play with the identification of roles, e.g., specific responsibilities within the relationship. Although this is important to document in a future agreement, early on it is important to know who to assess for certain key roles. There is a spectrum of decision-making authority that needs to be considered, from no decisions to all decisions being made by the contractor.
Knowing who is responsible for quality, who is the head production decision-maker, and who is the key contact are all pertinent points for making the right match for you and your business. These are going to be instrumental people to meet with and talk to during the development of a relationship, due diligence and later on. You must feel comfortable with the key people’s knowledge and personality. Trust must be built with the organization.
In your model, you can specify what the key positions are that you would like to see in their organization, but you usually cannot specify who performs these roles – this is the CMO’s responsibility.
Remember, if you partner with a CMO, you both have responsibility for the quality of a finished product.
Key Critical Activities
After identifying the key roles important within the relationship, the next step for a potential sterile manufacturing partnership includes identifying high-level criteria for a manufacturing process, such as equipment, process flow, and the quality activities supporting these. Here are some questions that could be included in your initial identification of the parameters you desire from a CMO:
- Is this a biopharmaceutical process? Does it include microbial or mammalian cell fermentation? Will you be utilizing stainless vessels or single-use, disposable polymer vessels?
- Will there be aseptic processing and/or terminal sterilization?
- Will there be lyophilization?
- Is there capability for vial, syringe, or cartridge production?
- Are there dedicated product contact parts, or are change parts necessary?
- Is the process highly automated? Will isolators or restricted access barrier systems (RABs) be first intent? What classification of cleanrooms do you want? Does their technology reduce aseptic connections and human intervention?
- Infrastructure: do you prefer an internal QC laboratory for chemistry and microbiology testing? Who performs microbiology and particulate monitoring?
- Facilities: is location crucial to your decision? Do you prefer to have a facility be domestic or geographically local? How many batches and what turn-around-time can be supported? What is cold chain capability and capacity (especially for biopharmaceuticals)?
- What is the CMO’s approach to client or visitor access? Is remote viewing available via webcam? How much oversight can you have?
Search and Selection
How would you find potential CMOs for your product or operation?
Information about capacity and capability is the key to making your search and selection process simpler. Identify core competencies and capabilities, and recognize the cost/benefit of requesting additional non-core activities (e.g., release testing or labeling) to be performed by the CMO.
The steps that follow provide information to accomplish the search. First, start with identifying the type of manufacturing you are interested in accomplishing. For instance,
- Classical pharmaceutical drug or biomolecules
- Separation of product types or custom manufacturing
- Clinical scale or commercial scale
- Scale-up capability (or not necessary)
- One stop shop’, or specific to manufacture only
- Advanced technology process or classical process
Secondly, find companies that may have these parameters you have selected. There are numerous resources today that offer differing levels of information and credibility in a CMO search. Some examples include word of mouth, past experience, web browsing, journal listings, journal advertisements, and conferences.
Thirdly, after developing an initial ‘long list’, try screening potential CMOs by phone or email, call and ask for literature, keep track and possibly try rating selections to further distinguish key parameters.
Sterile Manufacturing Model
Prior to choosing a CMO, it is useful to design a model for sterile manufacture that you desire at a CMO and use that model as a means of determining how well a potential CMO can fit your needs. It is best to understand what your minimum facility requirements are and to create a risk assessment for items that do not quite meet minimum requirements.
These could be considered user requirements criteria. These also add specifics to the intended design.
Some examples of determining criteria are:
- Who sources the excipients and components?
- Who releases the excipients and components?
- Whose procedures are documented (yours or theirs)?
- Who determines specifications?
- Bulk substance and/or finish-fill operations?
- Who tests/releases the finished product?
- Specify sterilization parameters
- Specify method(s) of environmental control
- Specify container and closure
- Specify inspection type for finished products
- Identify batch size for clinical or commercial products
- Who is responsible for project management activities (e.g., leading and administering meetings)
Communications
A structured communications process should be in place at the CMO, as well as between client and the CMO. Appropriate representation of critical areas should participate in meetings. Transparency, understanding and importance of topics for communications should define the frequency of meetings. Appropriate involvement of senior management can be beneficial. You must feel comfortable in the communication scheme. If the communication plan is not appropriate for your standards, ask the company to edit and update the plan. It also can be considered a best practice to share some information about the development program. Let the CMO know how important the program is to your company.
Issue Resolution
Having a plan for resolving issues is important to any relationship. Quite often and unfortunately, this plan is retroactive, like a poor CAPA (corrective and preventive action) process. If thought out well, it can be put in place for any CMO relationship, and just be customized for each particular client/CMO partnership.
Resolving issues for sterile manufacturing can be as simple as just contacting the CMO, or can be as complex as performing a thorough investigation for an OOS incident along with concomitant, ongoing communications.
Every issue that needs to be resolved has people involved, so people skills are crucial for both parties involved. Knowing the CMO’s procedure(s) for problem resolution is an important part of the selection process.
Importance of Microbiology in Due Diligence
At this point, you have your third party model in mind, and you have an outside view and understanding of what a potential CMO candidate has to offer.
With all the specifics you have in mind for your production needs, compliance needs, and sterile product perspective, an assessment is performed via desktop analysis or by a visit to the CMO. In writing or by phone, a request is sent to the CMO to respond as thoroughly as they can. In a due diligence visit, the same is accomplished by a single team or person who is skilled enough to ask the right questions and look for the key visible areas to help derive a decision for potential partnership. For a sterile operation, a due diligence decision cannot be made without a visit. Seeing a facility and its processes and being able to speak with the key people leading the organization are highly valuable points for making a knowledgeable decision.
A person with aseptic filling technology expertise and practical experience should co-lead the due diligence activity, with adequate support from a Microbiology function. If a microbiologist does not participate in the due diligence visit, then they should offer the person performing a due diligence visit some key points for CMO response. Microbiology is foundational to sterile manufacturing, so an understanding of this to generate accurate input from the CMO is crucial for due diligence decisions. The latter should not be taken for granted.
Figure 2. Due Diligence
Due diligence assessments should incorporate all the key parts of a potential partnership that will affect both business and scientific outcomes (Figure 2). This is a good overall list of the key areas important in the assessment. [7]
Microbiology, manufacturing and quality assurance only cover some of these areas. Yet, being aware of all the areas and how they interrelate in the assessment and decision-making can provide an important awareness for accomplishing an accurate assessment.
If you fine tune the assessment in each of these areas, it will make the final decision easier. And if a partnership follows, you will know the strengths, weaknesses, and opportunities to develop a strong, long lasting relationship.
It is difficult, but not impossible, to make judgment calls about a potential CMO for your business. The reasons for why we perform due diligence ahead of quality audits is often based on understanding of the business’s health and ability to accomplish our main objective of sterile product manufacture.
Business and Scientific Input
Even with the list of due diligence parameters mentioned earlier, certain criteria must be assessed to determine a CMO’s business health. Some examples of business input are:
- Determining the costs of manufacture
- Indicating if the site is at full capacity or is there capacity available
- Determining the rate at which they can they produce and release product
- Identifying existence of a change process, how changes are deployed, and their rate of implementation
- Determining if quality tools are used (e.g., lean and six sigma, root cause analysis, etc.)
- Determining if there is room for growth in capacity
- Determining if the business is growing
- Reviewing the organizational structure for value and effectiveness
Credibility and capability come from education and experience of the people within the CMO organization. Some examples of input on scientific expertise are:
- Education and experience background of leaders in the organization
- The training process for line operators and QC staff
- Experience and client scope for products being considered
Capability of the facility and processes are based on equipment, condition, and design. So, additional input is needed to determine manufacturing information, such as:
- Type of upstream processes available
- Type and size of sterilization equipment
- Type, speed and capacity of filling lines
- Depyrogenation procedures
- Preparation of components
- Frequency of equipment calibration and revalidation
- Changeover of products (cleaning, disinfection, sterilizationin- place processes and times)
People Assessment
We stated that credibility can be based on the knowledge and experience of personnel. For example, the manner by which personnel and management work together and their attention to procedural business is indicative of culture and values. Assessing the people ‘power’ of an organization can be enlightening. Ask a CMO if they have a code of conduct or ethics, and if the staff is kept informed and trained on ethical issues. Indications of how current the staff aligns with regulatory thinking in industry (domestic or global) can be determined by how a firm responds to agency inspection findings, and if it encourages live or virtual participation in external education to learn of current industry trends. Ask for examples of any recent agency GMP inspection reports. Because compliance can be domestic or global, with the latter preferred, a history of the CMO relating to ‘any’ compliance scrutiny would be valuable knowledge, as this can also provide clues to the CMO’s transparency.
While it might seem strange to consider personalities in the assessment, building a relationship with a CMO will involve interpersonal skills. You are looking for a good relationship fit as well as quality and technical.
Any information or indications that the CMO has credibility amongst top performers in industry would also be valuable information.
Process Assessment
It is also important to determine what the CMO has for:
- current process capability
- ability to meet global regulations, and
- current or planned advanced design.
There are a number of signifi cant indicators that can help you determine if a CMO you are assessing has kept up with state-of-the art thinking and technology for sterile manufacturing. The preventive maintenance program should be evaluated to determine if it is suffi cient. Determine if the Engineering department has access to the fi lling line for continuous improvement work or if it is restricted due to tight production schedules. Knowledge of the source and downtime record of the equipment helps evaluate continuity and integrity of the operation. An indication of the amount of risk taken is demonstrated in the approach to re-start of operations after media fi lls are performed.
Assess the CMO’s ability to meet grade-A continuity for aseptic processing, the approach to validation of fi ltration, terminal sterilization, and depyrogenation. Assess the approach to bracketing different clients’ container closure confi gurations and what is used for container and closure qualifi cation to support container closure integrity. Evaluate containment or separation of processes, such as single-use technology, currency of advanced practices such as steam in place or sterilization in place, types of gowning, and types of microbiological monitoring. A clear, simple and transparent approach is necessary for reviewing preventive actions for quality issues.
After the planned information gathering from the initial contact followed by the due diligence assessment, you should have identified one or two possible candidates to progress the relationship to the final stage prior to a written agreement.
Quality Audit
The Quality Audit is the final, demanding step for ensuring that the CMO is capable of performing what it states it is able to, and that can perform these actions within both cGMP compliance and the policies and needs of your company.
At this point in the process, you can have a good idea on how well the CMO communicates, although not under stressful conditions. Communication is one of the most important criteria in your selection process. If the firm has not demonstrated effective communication up to this point, there is certainly no need to perform a Quality Audit!
The due diligence assessment was key to determining information about capability and types of process and process controls at the CMO.
By the Quality Audit, we summarize how a team of expert scientists can assess the process and the process controls of the CMO.To approve the CMO, they must meet your company’s expectations At this point in the process, you can have a good idea on how well the CMO communicates, although not under stressful conditions.for level of compliance to cGMPs, as well as your company’s quality needs.
The CMO must meet your expectations for level of compliance for training of its staff as well as the experience and education that will produce credibility to you.
The facility, process design, and flow of personnel contribute to potential contamination issues. There must be adequate controls in place through procedures, fit-for-purpose design and the culture of the organization. If controls are adequate, then expectations are met. If not, then convey your concerns to see if any issues of risk for contamination will be mitigated and how/when that will occur. The company’s response could also indicate the level of interest in the working partnership.
A quality system must be in place to resolve quality issues thoroughly and expediently. The audit will examine if the operating staff follows their procedures. An evaluation can examine some examples of OOS (out of specification) or excursion investigations. The CMO must state in writing, in a Quality Agreement or contract, that they are to communicate to you punctually when ‘potential’ or real quality issues are identified. An understanding of how the CMO determines impact of quality issues across different clients’ products is crucially significant.
The latter are examples of important areas that the Quality Audit can evaluate in order to determine plausibility of a potential partnership.
Real Time Evaluation
Another area complementary to the quality evaluation is the industry’s new approach to an ongoing quality assessment. This usually occurs after the contract is signed and a partnership begins. Your organization should be innovative and develop a way to track the CMO partnership. The ongoing real-time quality evaluation can occur, for example, chronologically, or batch to batch, depending on the criteria and timetable within the evaluation. You can track information related to quality, such as EM (environmental monitoring) excursions, production metrics or batch quality metrics, on a periodic basis from records and communications from the CMO. Your results from this can lead to enhanced monitoring or a more liberal monitoring schedule.
Developing this quality tracking approach can prove to be valuable in sustaining a good partnership for the future.
Conclusion
The following is a summary of the steps suggested to improving success of a partnership with a CMO for manufacturing sterile drug products.
- Know about your third party model
- Understand the key roles and responsibilities for sterile CMO partnership
- Identify the specifics you require
- Identify potential CMOs to assess
- Perform due-diligence information gathering
- Select a potential CMO to audit
- Perform a Quality Audit to finalize your decision
- Draft agreement(s) and follow legal rules
- Track quality on a real-time basis
Following these steps can ensure a more robust and enduring partnership whose benefits will outweigh any costs over the duration of the relationship.
Glossary
FDA: Food and Drug Administration, U.S.
JFDA: Japanese Food and Drug Administration
MHRA: Medicines and Healthcare product Regulatory Agency , U.K.
MPA: Medical Products Agency, Sweden
Acknowledgement
We would like to thank our colleagues, Noel Long and Tim Nicoll, for their review of and input for this article.
References
- FDA Compliance Program Guidance Manual, 2010. U.S. Food and Drug Administration.
- Tuckman, Bruce W. 1965. Developmental sequence in small groups, Psychological Bulletin, 63
- Webster’s Ninth New Collegiate Dictionary, 1988. Merriam-Webster Inc., Springfield, MA
- Marra Jeff, 2012. Late Stage API Development, Manufacturing and CMO Relations, Pharm. Outsourcing, 13 (1),pp 12-18
- Schlender, Brent, 2012. The Lost Steve Jobs Tapes, Fast Company, May 2012 Issue 165
- Collins, Nate, 2011, Editors Message. Pharm. Outsourcing, 12 (5), p. 2
- Schmidt W. and I. Uydess, 2012. Smart Outsourcing: Strategic Alignment, Risk Management, and New Relationships, BioPharm. Int. Supplement, March 2012, pp 35-39
- Soelkner, Peter, 2012. What’s in a Game? BioProcess Int. 10 (3), pp. 22-25.
- Singer, Donald and T.J. Edkins. 2011. Contract laboratory partnerships, Contract Pharma. 13 (5)
- Ortiz, Braulio, et al. 2010. Increased FDA Scrutiny of Purchasing/ Supplier Controls, Contract Pharma, 12 (8), pp 100-103
- Langer, Eric S. 2011. Top 10 mistakes clients make with their CMOs, Contract Pharma, 13 (9), pp 36-39
- Choi, Leah and S. Rudge. 2010. 10 steps for choosing a contract manufacturer, BioProcess Int. 8 (8), pp 20-28
- EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use., 2013. Chapter 7 - Outsourced Activities. European Commission
- Long, Noel. 2013. Personal communication.
- Russell, J.P.,Ed.2005. The ASQ Auditing Handbook. Quality Press, Milwaukee, WI
Donald C. Singer is Global Lead Quality Manager, Microbiology R&D for GlaxoSmithKine. Don is a member of the USP Microbiology Committee of Experts, Certified Specialist Microbiologist (NRCM) and Certified Pharmaceutical GMP Professional (ASQ). Don’s career spans over 35 years of research, quality control, quality assurance experience including over 25 years in the pharmaceutical industry.
Terrence Walsh, RPh, MBA is an investigational supply chain professional who is currently on secondment from GSK to TransCelerate. He has 25 years’ experience in the pharmaceutical industry. He has worked at NIH, CR/MOs and GSK. He also keeps his pharmacy license active and works 1 weekend per month at a small independent pharmacy.