Anthony M. Cundell, PhD- Microbiological Consulting, LLC, Rye, New York ; Dennis E. Guilfoyle, PhD- Johnson & Johnson, New Brunswick, NJ
Introduction
Pharmaceutical and Medical Device companies often use Contract Manufacturing Organizations (CMOs) for new product development, to procure services that they may not have expertise or facilities internally, manage their limited financial resources, manufacture smaller batches of clinical supplies, or obtain additional manufacturing surge capability. For example, the role of CMOs was critical in the launch of COVID-19 vaccines in the short 11 months from the SARS-CoV-2 RNA virus base sequencing to the FDA emergency authorization for vaccine shipment. However, the authors in their different roles as an industry consultant and a corporate regulatory compliance professional have encountered chronic issues with CMOs and associated contract testing laboratories not fully disclosing requested information to their clients that they view as proprietary or at least confidential. Often there appears to be a fundamental clash over the ownership of the information. To scientists like us who have marginal legal training, with emphasis on current Good Manufacturing Practices (cGMPs), perhaps naively, we believed “He who pays the piper, calls the tune.” Obviously, the issue is more complex than that.
Why might the client want more information from their CMO? Reasons may include it is needed to complete regulatory submissions, for quality oversight, failure investigations, help expedite a project, ease supply chain concerns, or for future technology transfer to a company manufacturing site after product approval.
Why might the CMOs be reluctant to provide more information? With multiple clients with differing demands they want to remain flexible, and not establish an excessive and costly quality system representative of the most demanding client or, more to the point, different procedures for each client which would be a nightmare to administer. Furthermore, non-disclosure agreements with other clients may constrain the free exchange of information. Or perhaps, they are not prepared or capable of supplying this information because of a lack of data tracking system for testing and manufacturing deviations or inadequately trained personnel to respond to the request. Is this a real CMO concern or are they merely protecting their business? We believe that a well-written Quality Agreement between the two parties has prevented this cGMP gap and improves the quality of the investigations and their documentation. Within the conclusion of this article, the authors recommend key elements that should be included in a contract laboratory quality agreement.
Pertinent Good Manufacturing Practices and ICH Guidance for Industry
The current Good Manufacturing Practice (CGMP) Regulations are clear on this issue. Direct references to contractors are in bold. 21 CFR 211.22 Responsibilities of quality control unit states: “The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed or held under contract by another company”
To address their concerns, the FDA published the 2016 Guidance For Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements that provides a quality systems approach, which recommends how a pharmaceutical company and their CMOs can meet their joint CGMP responsibilities. The Guidance for Industry states the following:
“If an owner employs a contract facility for all or part of the manufacturing (including processing, packing, holding, or testing) of a drug or drug product, the owner’s quality unit is responsible for approving or rejecting the contract facility’s product or service. The contract facility is also required to comply with statutory CGMP and applicable CGMP regulations, including requirements for its quality unit. CGMP regulations require that quality unit activities and procedures be in writing, and that these procedures be followed.”
“Implementing a written quality agreement can facilitate compliance with CGMP and, in particular, with 21 CFR 211.22(d), which states that quality unit activities and procedures should be in writing. FDA recommends that owners and contract facilities establish a written quality agreement to describe their respective CGMP-related roles, responsibilities, and activities in drug manufacturing.”
On October 2021 FDA published a Compliance Program 7356002M, entitled Surveillance Inspections of Protein Drug Substance Manufacturing. In this document they state “Applicants and contract manufacturers should work together to establish and maintain appropriate quality oversight of contracted manufacturing operations. ICH Q10 recommends that owners and contractors define the responsibilities and communication processes for the quality related activities of both parties and document these in a written agreement. Guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (November 2016) provides recommendations on the content of such agreements.”
There are several ICH Guidance documents for Industry that contains the recommendation for the inclusion of well-defined Quality Agreements between product owner and their CMOs. This ICH Guidance includes: Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; Q9 Quality Risk Management and Q10 Pharmaceutical Quality Systems. Among these three documents, the ICH 10 is the most comprehensive and specific for describing the essential components that should be evaluated and included between the owners and the contract facilities.
483 Observations in the Absence of Robust Quality Agreements
We have found in Form 483 Observations received by a drug manufacturers requests to supply confirmation that the analytical methods employed internally and by contract testing laboratories were adequately validated as alternative methods to compendial methods or if a compendial method meets the method qualification requirements as described in the official test method. The client conducted a comprehensive review of the analytical methods used for release and stability testing. When contacted to supply assay validation reports, the contract testing laboratories were not cooperative claiming that the information was confidential. Partial blame for this outcome lay with the client not performing their due diligence before their arrangement had been agreed upon. However, when unforeseen conditions change, as with the case of the FDA 483, the client is at a disadvantage by policy decisions by the management of the contract laboratory around disclosure.
In another case, in response to an out-of-specification (OOS) result generated by a CMO testing laboratory, the only documentation that the CMO was initially willing to provide was a high-level investigation report and not the original lab report, assay and laboratory investigation standard operating procedures, investigation check list, and method qualification. This limited document assumes that their investigative report is unbiased and scientifically sound in the assessment of their analytical data and internal operation and practices. Unfortunately, company self-interest must be assumed without the availability of the original data for review. This is in alignment with the saying “In God we trust, everyone else should bring data”.
Warning Letters Associated with Quality Agreements
Porton Biopharma, Ltd, Porton Down, Salisbury, UK – January 19, 2017
This was the first warning letter issue after the finalization of the Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. The FDA put the industry on notice that Quality Agreements are an expectation as written documentation and they must be actionable and recognize the joint responsibility for CGMP compliance.
The warning letter stated: “Firms acting as contract manufacturers must comply with CGMP. FDA is aware that many pharmaceutical product manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.”
“You and your customer, Jazz Pharmaceuticals, have a quality agreement regarding the manufacture of Erwinaze®. Regardless of this agreement, you and Jazz Pharmaceuticals are both responsible for the quality of drugs released and ultimately administered to patients. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity.”
VitaPurity Corporation, Central Point, Oregon – May 12, 2017
This regulatory action illustrates that the dietary supplement company believed “when ignorance is bliss, it is folly to be wise
The warning letter stated: “You receive finished, packaged and labeled dietary supplements from a manufacturer that manufactures the dietary supplements on your behalf (your contract manufacturer). You hold and distribute the dietary supplements. You state that you specify the active ingredients and their proportions for each of your products. . . . You state that you assume your contract manufacturer is responsible for preparing a master manufacturing record, exercising quality control functions, and verifying that the finished products meet specifications. You state that you assume your contract manufacturer is complying with 21 CFR Part 111 because you are unaware of any problems at the plant. You state that you do not have a written agreement with your contract manufacturer, and have not performed any audit or engaged in any other activity to determine the acceptability of the manufacturer to manufacture your dietary supplement products, or to ensure the quality of the dietary supplements received and that the products are packaged and labeled as specified in the master manufacturing record”.
Vilvet Pharmaceutical , Chester Springs, PA— February 25, 2019
In this regulatory action, a Quality Agreement was in place but the company did not take responsibility verifying that the product manufactured by the CMO met specification.
The warning letter stated: “Your firm failed to establish adequate written responsibilities and procedures for reviewing batches made by your supplier. You also failed to review each batch produced for you to determine its appropriate disposition (i.e., reject or approve).”
“Your firm used a contract manufacturer (also referred to as supplier), to perform manufacturing, processing, and packaging activities for drug products on your behalf. In your quality agreement with contract manufacturer you stated that both you and your supplier are responsible for complying with 21 CFR 211.22. However, the quality agreement further specified that your supplier is responsible for approval or rejection of all products.”
Contributing Factors that are a Challenge
With the advantage of having a combined 90 years of regulatory and pharmaceutical industry experience the authors have a few observations regarding today’s current inconsistent expectations from contract manufacturers and laboratories. This is not a reflection of all established facilities and certainly not a summary of any one specific CMO, but simply a collection of conditions that we believe currently exists today.
Because of the limited number of experienced laboratory managers, superiors and analysts, we see that the depth and thoroughness of laboratory OOS investigations are shallow and incomplete, quite like the findings of many FDA 483 observations documented over the years. This shortage may not be totally the fault of the contract laboratories but attributable to lack of academic curriculum on industrial microbiology and employee departures to better paying jobs after several years of laboratory experience. This lack of education, experience, and training of the basic principles of the microbiological methods makes investigating analytical anomalies a challenge for microbiologist and QC personnel. Perhaps this educational gap is exacerbated by a lack of regulatory guidance regarding what is expected within a Quality Agreement for a microbiological investigation. Past regulatory findings as described in the above section clearly show that these specific investigative laboratory reports to detect analytical and equipment error has been dubious and even occasionally fraudulent. This shortcoming should be significantly remedied by the recent publication of the PDA- TR 88 entitled “Microbial Data Deviation Investigations in the Pharmaceutical Industry”, which these authors had contributed.
Recommendations
Clearly, the FDA sees the lack of relevant quality agreements between pharmaceutical companies and their CMOs as a cGMP compliance gap. Pharmaceutical and Medical Device companies must determine that the compliance level of future partners adhere to the required standards by on-site audit or at least a questionnaire when selecting a CMO. A comprehensive and binding Quality Agreement must be carefully developed employing experienced members of the laboratory and Quality department, signed, preferably linked to the business agreement, so cGMP compliance is a part of the performance measurement. Some key laboratory components that should be part of a Quality Agreement would include:
- A communication plan that explains how laboratory deviations will be relayed to the client by the contract laboratory, and how such deviations will be formally investigated, documented and resolved. This would require a pre-existing protocol for how this will be completed.
- The communication plan should include the verbal and written correspondence between the client and contracted facility, including the allowable delay between the discoveries of OOS analytical results and alerting the client.
- It should be specific which party will be responsible to carry out validation, suitability testing, qualification of equipment systems
- And most importantly the Quality Agreement should include who will be responsible and qualified to perform the investigating deviations, discrepancies, failures and OOS results in the laboratory.
This would allow for poor cGMP compliance to be subject to financial penalties or even contract cancellation. CMOs must acknowledge their client’s cGMP responsibilities and respond favorably to requests for information that include professionally performed investigations.
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