Pharmaceutical Companies and Contract Manufacturing Organizations Relationships: What to Learn from FDA Warning Letters

    Today, many pharmaceutical companies operate on an outsourcing model. This is very common for companies who are evolving from being mainly development-focused to a point where they are entering latter stages of Phase 2 or Phase 3 clinical trials, and plan to have a product ready for market approval in the coming months.

    Effective Quality Oversight of Pharmaceutical Contract

    The FDA can inspect the Pharmaceutical Companies and Contract Manufacturing Organizations (CMO) anytime without prior notice to validate if the manufacturer is in full compliance with GMP and has complete, documented control over their:

    • Manufacturing Facility
    • Equipment
    • Raw Materials
    • Operating Procedures (SOPs)
    • Staff Training
    • Quality of Finished Products
    • Quality Management System

    FDA inspections can result in warning letters to persons or organizations for violations of regulatory requirements. Typically, the nature of FDA warning letters is informal and advisory. A warning letter provides timeframe for the company to inform FDA of its plans for correction. Its goal is to provide prior notice, and establish voluntary compliance with the law. If the violation is not adequately corrected, it can lead to serious consequences and enforcement actions.

    Learning from Examples

    Warning Letter Example #1

    FDA reported flaws at Emergent facility making Johnson & Johnson Covid Vaccine. New production was halted at the FDA's request, according to a joint statement by Dr. Janet Woodcock, acting FDA commissioner, and Dr. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research.

    "For the vaccines already manufactured, the products will undergo additional testing and will be thoroughly evaluated to ensure their quality before any potential distribution," Woodcock and Marks said. "We will not allow the release of any product until we feel confident that it meets our expectations for quality."

    Johnson & Johnson is riding the negative news splashed across headlines and Emergent BioSolutions is to Respond to FDA's Form 483 'Within Days'

    In wake of Emergent's vaccine problems, CEO's stock trades come under scrutiny.

    Warning Letter Example #2

    Tris Pharma, a CMO for Pfizer Hit by FDA Warning Letter for ADHD Drug

    The FDA, in an unusual move, named Pfizer in the letter.

    "You and your customer, Pfizer, have a quality agreement regarding the manufacture of drug products," the agency said. "You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with application sponsors."

    "After this investigation, you attributed the leaks to a specific lot of caps that had cracks in their liners and remained in inventory for an extended time without retesting," the FDA said in its letter. "Your response is inadequate. Defective product remained on the market for an additional eight months before you completed a thorough investigation and initiated a recall in July 2017."

    Warning Letter Example # 3

    Health Pharma USA LLC Hit by FDA Warning Letter for Significant Violations of Current Good Manufacturing Practice (CGMP) Regulations

    The main deficiencies pointed out in the warning letter include:

    • The firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
    • The firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188)
    • The firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and your firm's quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).
    • The firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2))


    1. A frequently cited FDA observations includes a shortage of written policies, closely followed by a complete lack of evidence of a quality system and quality system failures. At least, the CMO must be able to produce documented evidence of:
      • Availability of written procedures
      • Well-defined CAPA process
      • Definitive product design controls
      • Purchasing controls that include Approved Supplier List
      • Process validation plan
      • Production record review
      • Testing and release plans, including stability testing of components, containers and closures
      • Documented product complaint files
      • Definition of the responsibilities of the quality unit
    2. Making the right choice of CMO for your organization is critical. If you get it right, you can build a sustainable, mutually beneficial relationship. If you get it wrong, the consequences can be both disruptive and costly. It can create regulatory burdens, cause delays and even damage your company's reputation.
    3. Strong level of communication must exist between the pharmaceutical company and the CMO. For smooth and sustainable partnership, communication must be clear and effective from the get-go.

    Training for Companies that Use Contract Manufacturers and/or Contract Laboratories

    Attend our 2-day virtual seminar Quality and GMP Compliance for Virtual Companies. In this seminar you will learn the requirements and expectations of major health care regulators that are applicable to "virtual" companies. You will learn how to diagnose your company's needs based on which GMP and GCP-governed operations you retain and which you outsource; what the current expectations and best industry practices are for selecting, qualifying and monitoring your contractors to ensure they are meeting your requirements; and how to build a quality system framework that is not excessive for your current needs, but has the structure and integration to "grow with you" as the scope of your operations change.