Contamination control has long been one of the major challenges in pharmaceutical production. Nothing is a greater liability to patient safety. Companies with multiple products have always had to develop and validate strategies to ensure adequate cleaning between batches of different products. With the increasing trend towards outsourcing manufacturing to contract manufacturing organizations (CMOs), however, the concern about—and urgency for—contamination control has skyrocketed in recent years.
By definition, a CMO is a multi-product facility. Not only does it have to develop its own contamination prevention procedures, it also has to accommodate the requirements of each of its clients. Both industry and regulatory authorities are catching up with the dangers associated with CMO outsourcing, and regulation and guidance documents are being published to deal with this increasing challenge to drug safety.
The need for contamination control is nothing new in the pharmaceutical industry, and has been reflected in regulatory authority GMP regulations for years. The U.S. Food and Drug Administration’s (FDA) GMP Regulations, written in 1978, state “There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mix-ups.”1 The European Medicines Agency (EMA) GMP Regulations have similar language: “In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated, and self contained facilities must be available for the production of particular medicinal products. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made.”2 Even more recent publications, such as the new Chinese GMPs, cover this topic, “A comprehensive consideration of the aspects such as properties of products, processes, and intended uses etc. should be given, so as to determine the feasibility of sharing premises, facilities, and equipment for different products, along with an assessment reports.”3
Similarly, the 1978 U.S. GMP Regulations recognized the need for containment of penicillin production: “Operations related to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.”4 The widely accepted ICH Q7 GMP for Active Pharmaceutical Ingredients— from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use—broadens containment requirements beyond penicillin: “Dedicated production areas, which can include facilities, air handling equipment, and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins. The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved unless validated inactivation and/or cleaning procedures are established and maintained.”5
Most of these regulations, however, were originally written with in-house manufacturing in mind. The shift from in-house production to CMOs around the world has caused the industry and regulatory authorities to reevaluate the need for additional guidance and regulation surrounding prevention of contamination in multi-client, multi-product CMO facilities. A 2011 survey of biopharmaceutical manufacturers and CMOs conducted by BioPlan Associates (Rockville, Md.) revealed that “managing cross contamination has increased the most among 19 factors of great importance to drug sponsors as they evaluate contract manufacturers.”6 In the survey, 52.3% responded that effective handling of cross contamination issues was ‘very important’ and 33% said it was ‘important’.7
Industry and industry organizations have already started to address these challenges. The International Organization for Standardizaion (ISO) is currently revising sections of ISO 14644, Cleanrooms and Associated Controlled Environments, specifically those sections dealing with monitoring and periodic testing to prove continued compliance, and classification of air and surface cleanliness. In September 2010, the International Society for Pharmaceutical Engineering (ISPE) published its Risk-Based Manufacture of Pharmaceutical Products (aka Risk-MaPP), which applies ICH Q9 principles specifically to successful containment analysis and strategies for multi-product facilities. It provides a model using all the stages of risk management: risk assessment, risk identification, risk analysis, risk evaluation, risk control, risk reduction, risk acceptance, risk review, and risk communication. CMOs can benefit from this approach just like their client companies.
Stephanie Belly Wilkins, one of the authors of the Risk-MaPP document and president of PharmaConsult US, Inc., a Bridgewatger, N.J.-based consultancy that specializes in providing global regulatory support to clients in risk management for cross contamination, recently commented, “We have several CMO clients that have applied the Risk-MaPP principles. The CMOs not only have to satisfy the regulatory agencies’ requirements, but their clients’ as well. Many times the clients are more difficult to convince because they have preconceived notions on the requirements of the agencies. FDA and EMA are looking to scientific risk based methods to determine whether multi-product facilities are manufacturing safe products.” She also noted that “the CMOs that are applying Risk-MaPP principles to their operations also find this to be a competitive advantage.”8
The European Union has taken the lead in initially addressing this growing trend toward outsourcing in general via regulation; its current GMPs contain a section on Contract Manufacture and Analysis. The United States followed suit by adding a new topic subsection, Control Outsourced Operations, to its guidance document Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations.
However, both of these documents focus primarily on the definition of responsibilities in the contract; they do not specifically address the inherent increased risk of cross contamination in a multi-product facility. Most recently, the EMA has recognized there is still a gap in regulatory guidance in this area. In June 2012, they are set to release a new draft guidance on the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities. This document is the result of the realization that, as defined in the concept paper’s problem statement, “there is no defined approach in order to outline a method of deriving acceptable exposure limits for cross contamination between products manufactured using shared facilities.” 9 The proposed approach will also borrow from risk management principles contained in ICH Q9. Its goal is to recommend a scientifically based assessment process to determine if a product should be manufactured in a dedicated facility.
The FDA has also noted problems arising from the growing trend toward outsourcing to CMOs with some dismay. Rick Friedman, director of the manufacturing and product quality division at the FDA’s Center for Drug Evaluation and Research (CDER) has commented that the agency thinks “that the industry has done an uneven job of selecting and managing contractors.”10 Over the past few years, it has been reported that the FDA is considering issuing a new guidance document with more detail on how the agency expects industry to select and manage outsourcing relationships. One report even stated that “the FDA is considering making drug makers even more accountable for problems at their manufacturing partners, for example by sending warning letters to the contract giver as well as the contractor if a deviation is discovered during an inspection.”10
The pharmaceutical industry has a general model in place for monitoring CMOs: supplier certification. But what is the best strategy for the CMO to use to address these growing client and regulatory concerns about cross contamination issues? The best approach is for the CMO to acknowledge the situation and proactively develop a well thought out and clearly documented general policy framework with supporting procedures to deal with these challenges.
The new regulatory agency regulations and guidance documents along with the principles espoused in ICH Q9 and ISPE’s Risk-MaPP provide excellent direction. If the CMO has done due diligence in performing its own risk analysis, and then developed a robust internal procedural framework for preventing cross contamination, it will be much easier to overlay individual client requirements and create an efficient and compliant quality system for each project.
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Figure 1 shows a model for combining client and CMO methodologies together to create a robust quality system approach to prevent cross contamination. In addition to typical actions such as establishing requirements for ongoing monitoring, detailed documentation, and periodic internal and supplier audits, as part of finalizing the contract for any new client product, the CMO and client should jointly complete an established risk assessment instrument covering the specifics of that assignment, and should agree, in writing, on the details of how the process should be monitored and handled. Equally important is periodic, comprehensive, documented CMO employee training on the CMO policies, supplemented with individual pre-project training on the detailed requirements of specific client processes. This approach, together with a hopefully excellent inspection and audit record, should go a long way towards easing a potential client’s anxiety surrounding the CMO’s ability to prevent cross contamination. It should equally satisfy any concerns of inspecting regulatory authorities.
Recent headlines and reports of contaminated raw materials and concern over rapidly multiplying offshore CMOs that have not been inspected are pushing regulators to address this significant threat to pharmaceutical product safety via new guidance documents. Client companies and CMOs have the ability to address these challenges proactively. The history of drug law is clear; tightened regulation is often the result of major tragedies. Let’s hope history doesn’t repeat itself.
- 21CFR211: Current Good Manufacturing Practice for Finished Pharmaceuticals, “Subpart C (Buildings and Facilities), 21CFR211.42(c)”, Apr. 1 2011. U.S. Food and Drug Administration. Accessed Feb. 21, 2012, http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1
- EudraLex – Volume 4 Good manufacturing practice (GMP) Guidelines, “Chapter 3 Premises and Equipment, 3.6”, 8 Oct 2003, European Medicines Agency, Accessed Feb. 21, 2012, http://ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/cap3_en.pdf
- Good Manufacturing Practice (GMP) for Drugs, “Chapter 4 Premises and Facilities, Article 46”, 19 Oct 2010, Chinese State Food and Drug Administration, 21 Feb 2012, http://eng.sfda.gov.cn/WS03/CL0768/65113.html
- 21CFR211: Current Good Manufacturing Practice for Finished Pharmaceuticals, “Subpart C (Buildings and Facilities), 21CFR211.42(d)”, 01 Apr 2011, US Food and Drug Administration, 21 Feb 2012, http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1
- ICH Q7, “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients”, 10 Nov 2000, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 21 Feb 2012, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf
- Miller, George, “Contamination Concern Rises about CMOs,” 30 Nov 2011, Fierce Pharma Manufacturing, 21 February 2012, FierceMarkets, http://www.fiercepharmamanufacturing.com/story/contamination-concern-rises-about-cmos/2011-11-30
- Langer, Eric, “The CMO/Client Connection: What Makes It Work?”, Apr 2011, Life Science Connect, 21 Feb 2012, http://www.lifescienceconnect.com/index.php?option=com_content&view=article&id=99:the-cmoclientconnection-what-makes-it-work&catid=47:marketing-insights&Itemid=188)
- Online interview, 12 Feb 2012
- “Concept Paper on the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities,” 20 Oct 2011, European Medicines Agency, 21 Feb 2012, http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/10/WC500117225.pdf
- Taylor, Phil, “The FDA Interview: Is pharma getting worse at manufacturing?” 29 Sept 2010, InPharm, 21 Feb 2012,
Elaine Lehecka Pratt is industry professor in the Pharmaceutical Manufacturing graduate program of Stevens Institute of Technology in Hoboken, N.J., and Founder/President of Lehecka Pratt Associates, Inc., a regulatory compliance consultancy. She has more than 30 years of experience in the pharmaceutical industry and specializes in regulatory compliance, quality, and training issues. Lehecka Pratt Associates, Inc., 908-889-8162; firstname.lastname@example.org, www.lpa-training.com.