Francis Goodwin, director of the FDA’s Division of Drug Quality II, Office of Manufacturing Quality, Office of Compliance, spoke about enforcement trends at the Parenteral Drug Association (PDA)/FDA Regulatory Conference in September. He addressed warning letters, import alerts, and regulatory discretion activities. Let’s focus on warning letters, where the top concerns he presented were data integrity and contract manufacturing. His presentation identified that more than five warning letters issued in 2017 were issued to firms operating in this space, either as contracted facilities, product owners, or both.
This two-part article will address how sponsors can effectively ensure confidence in data integrity at their contract development and manufacturing organizations (CDMOs) and have confidence in the information upon which they base lot release decisions. In this first installment, we cover 2017 enforcement actions (effective as of October 31, 2017) and identify things that can go awry in contractual relationships. Note that the focus here is on data integrity in contractual relationships and is not meant to address all the factors that should be considered when selecting a contract manufacturer or laboratory.
FDA Enforcement Of Data Integrity In Contract Relationships
Let’s begin with 13 warning letters from 2017 that mentioned contract operations. The table below identifies the warning letters. (See the appendix for the relevant text for the deficiencies in question.) This reflects 16 percent of the 69 warning letters issued in FY2017 to API and drug product manufacturing sites. These warning letters were not identified or described in Goodwin’s presentation slides at the PDA/FDA meeting. One pair was mentioned briefly during the presentation, and it was clear which firm(s) was being discussed.
|Contract Manufacturer/Laboratory||Associated Sponsor|
|Porton Biopharma Limited||Jazz Pharmaceuticals, mentioned in the warning letter as sponsor for the product in question, did not receive a warning letter.|
|Badrivishal Chemicals & Pharmaceuticals||None identified|
|Lumis Global Pharmaceuticals Co. Ltd.||None identified|
|Indoco Remedies Limited||None identified|
|Shandong Analysis and Test Center||None identified|
|ChemRite CoPac, Inc.||Sage Products Inc also received a warning letter that mentioned ChemRite CoPac.|
|Raritan Pharmaceuticals, Inc. also received a warning letter, but it did not mention their contract manufacturing operations.|| Homeolab USA Inc.|
|Hetero Labs Limited Unit V||None identified|
|Meridian Medical Technologies, Inc. a Pfizer Company||Mylan is sponsor for the product in question, is identified as such in Meridian’s warning letter, but did not receive a warning letter.|
|No mention of the firm from which they purchased the component [presumably an API] under import alert.||Aztex Enterprises Ltd. used a component that came from a firm under import alert to manufacture an OTC drug.|
|Accelerated Analytical Laboratories Inc. is a contract testing laboratory.||None identified|
The contract manufacturing/testing site is responsible for operating consistently with the governing CGMPs. The company for which they manufacture is ultimately responsible for the quality of the product and to ensure the contract firm is CGMP-compliant. Clearly, Sage Products was held responsible for the failures at their contract manufacturer, ChemRite CoPac, and both received warning letters. Porton BioPharma received a warning letter that mentioned they made process changes prior to receiving FDA approval, but the sponsor, Jazz Pharmaceuticals, did not receive a warning letter for distribution of a drug for which process changes were not reported to the FDA. Lumis Global Pharmaceuticals was cited for accepting an API from a supplier under U.S. import alert, relabeling the API as if they manufactured it, and distributing it to the U.S. It’s not clear whether any of their customers were aware of their practice before either the form 483 or warning letter was issued. Indoco Remedies failed to provide its customers with information necessary to make a decision regarding the need to submit a field alert report (FAR), even though their quality agreement had that provision. The warning letter to Homeolab clearly mentioned the deficient activities at their contract manufacturer, Raritan Pharmaceuticals, for which they appear to have failed to provide adequate oversight. Although Raritan received a warning letter in June 2017, it did not mention the services they provide as a contract manufacturer. Aztex Enterprises purchased a component under import alert [probably an API] and used it to manufacture a product that was shipped to the U.S. The firm under import alert was not named in the warning letter. And, finally, Accelerated Analytical Laboratories operates a contract testing service for OTC drugs and failed to select suitable tests and validate them. The firms whose products they test were not identified.
This year, FDA enforcement actions appear to make a point that the contractor is meant to be an extension of the firm sponsor that offered the contract. Until the FDA takes enforcement against or all partners in these business relationships, problematic behavior will continue and patients will remain at risk. This FY saw at least two instances of paired warning letters issued to sponsor and contracted organization: Sage Products and ChemRite CoPac, and Homeolab and Raritan. From the text in the other warning letters in the appendix, other sponsors are clearly involved.
This is not a new issue. In the 2010, a form 483 issued to McNeil Healthcare stated in observation 7 that Microanalytics, a contract laboratory, performed testing for the uncharacteristic odor found in some solid oral dosage forms. Commenting on the review of data from the contract laboratory, the FDA said:
“The chromatograms, spectra and records were not reviewed by a second person [at the contract laboratory] to assure that the records comply with specifications. Additionally, your Quality Unit failed to review the data for errors. [emphasis added] For example, some of the chromatograms showed the acquisition date as May 2003. However, the actual analysis was performed in September 2009. There is no assurance that the data provided is accurate and reliable. …”
In 2011, the FDA issued a warning letter to Nanjing Maohai Biotech Co. The firm sent samples to a contract laboratory for testing. The warning letter stated:
“Your firm lacks raw data to demonstrate that the (b)(4) test for the lots of (b)(4) shipped to the United States met the acceptance criteria. … All documents related to the testing of your (b)(4) should be reviewed and approved by your quality unit according to established procedures. [emphasis added]. Contract laboratories are an extension of your operations, and, as such, your quality unit is responsible for all data acquired at the contract laboratories you choose to use.”
Regarding testing that was performed in support of investigations into product complaints, in the same warning letter, the FDA stated:
“Your firm indicated that the (b)(4) had passed the X test conducted by your contract testing laboratory. However, raw data pertaining to the test and retest performed by your contract laboratory was not available for your review and possible determination of root cause.” [emphasis added]
Form 483 inspection observations and warning letters frequently cite 211.194, “failure to review complete data from all tests. …” In general, this is cited when firms fail to review electronic data and their associated critical metadata (i.e., audit trails). This is a point at which contract manufacturing, testing, and data integrity concerns can intersect.
What Can Go Awry
It is clearly unreasonable to expect firms to review original data, either process data or laboratory data, generated by their contract manufacturer as they decide to release each lot of API or drug product. It is equally unreasonable for a firm to review dozens of pages of paper a contractor might send to represent some of the data, albeit not original data, for each chromatogram. Further, some virtual firms may not have individuals with the expertise to do so and are left with a false sense of security about their contract site … they generated and sent us all this “data,” so it must be correct. Let’s consider how the sponsor can make lot-release decisions with confidence based on data from their contracted partner.
First, there are any number of ways to get this wrong:
- FDA inspections and enforcement actions have identified instances where firms have never performed an on-site evaluation of their contract manufacturer.
- Equally problematic, and perhaps more common, are on-site audits that are superficial or performed by auditors who do not have deep GMP expertise or training and experience in how health authorities are currently evaluating data governance within the GMP system.
- Depending on the geographic location of the contracted site, periodic visits may be infrequent or not happen at all, even if a qualifying visit was conducted.
- The sponsor firm has not determined how data and information will be transferred from their contract site in a manner that ensures its integrity. Is it done through routine email, or is there a secure means of transmission of this very important data?
- The sponsor firm has not documented the information they require to make a lot-release decision. Will it be done exclusively on a certificate of analysis, or will copies of some data be necessary … and which data and why?
- Quality agreements don’t adequately address responsibilities for all GMP activities between the parties.
Examples earlier in the article cite warning letters issued to contract manufacturers and laboratories followed by a related warning letter issued to the firm that contracts for their services. Personally, I think this is long overdue. It is the industry’s responsibility to ensure we contract only with partners that have adequate systems in place to manufacture and test consistent with CGMPs in a manner that ensures product quality and patient safety. This includes having systems in place to ensure trustworthiness of data, as we describe in part two of this article.
Part 2 will address the health authority GMP guidance on contractual relationships and will share best practices related to data integrity oversight at contract sites.
Appendix: FDA FY2017 Warning Letters That Mention Contract Operations
|Manufacturer/ Laboratory, Date||Warning Letter Relevant Text|
|Porton Biopharma Limited, January 19, 2017||You manufacture Erwinaze under contract on behalf of Jazz Pharmaceuticals, which holds the Biologics License Application for Erwinaze. The process changes discussed above were not approved by FDA before you manufactured, or your customer, Jazz, distributed, Erwinaze. Specifically, working cell banks (b)(4) were used in commercial production prior to approval. These working cell banks were not reviewed and approved by the Agency for their suitability for Erwinaze manufacture, even though the changes in the source material or cell line have a substantial potential to adversely affect the identity, strength, quality, purity or potency of Erwinaze.|
NOTE: Jazz Pharmaceuticals has not received a warning letter for failure to report the changes to FDA.
|Badrivishal Chemicals & Pharmaceuticals, March 2, 2017||3. Failure to verify the suitability of analytical methods.|
You failed to ensure that the methods used by your contract testing laboratory, (b)(4), have been verified as suitable for their intended use. It is your responsibility to use a qualified contract testing laboratory that produces accurate and reliable results.
Your firm contracts with (b)(4) for release testing. Your quality assurance agreement with (b)(4) does not specify method validation responsibilities. During the inspection, our investigators requested the method verifications for the residual solvent, impurity, and microbiological tests performed by (b)(4). You stated that the requested documents were located at (b)(4) and that you would retrieve them within 15 days.
In your response, you did not provide the requested documents from (b)(4), but instead provided draft protocols for the residual solvent, impurity, and microbiological testing. You stated that these protocols would be verified by December 15, 2016, but it is unclear which company would perform the verification experiments.
Your response is inadequate. In response to this letter, clarify which company performed the verification. Also, provide the results of an internal review of all the other test methods for your drugs to determine the need for method verification or method validation, as appropriate. If verification or validation is needed, provide a timeline for completion and the company that will perform the verification or validation.
NOTE: Their customers are not identified.
|Lumis Global Pharmaceuticals Co. Ltd., March 2, 2017||Shipping drugs from a manufacturer on FDA Import Alert 66-66|
(b)(4), one of your suppliers, has been on Import Alert 66-66 [“APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet the Requirements For The Labeling Exemptions in 21 CFR 201.122”] since (b)(4), specifically for their (b)(4) USP API. However, you shipped (b)(4) USP API manufactured by this firm to the United States in February 2015 and declared that you were the manufacturer on importation documents.
NOTE: Their customers are not identified.
|Indoco Remedies Limited, March 27, 2017||2. Your firm has failed to ensure the responsibilities and procedures applicable to your quality control unit are followed (21 CFR 211.22(d)).|
Under your quality agreement with your customer, (b)(4), you must notify them within (b)(4) if your firm determines that any batch of distributed drug product should be subject to a field alert report (FAR). However, at the time of the inspection, there was no evidence that you had sent this notification to your customer although numerous complaints had been received for multiple lots regarding leaking, empty, and under-filled bottle defects. Your failure to follow the provisions of your quality agreement and appropriately notify your customer of the quality problems discussed in this letter may have delayed your customer’s ability to take important actions to ensure the quality, safety, and efficacy of its products, including notifying FDA via a FAR under 21 CFR 314.81. We note that (b)(4) submitted a FAR after the close of our inspection of your facility.
NOTE: Their customers are not identified.
|Raritan Pharmaceuticals, Inc., June 20, 2017||NOTE: The warning letter does not address that they function as a contract manufacturer nor does it identify Homeolab USA Inc., although the Homeolab warning letter does identify Raritan as the contract manufacturer.|
|Shandong Analysis and Test Center, June 22, 2017||Failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.|
Your site is a contract testing lab [emphasis added] that analyzes samples of heparin and heparin-related drugs for the presence of over-sulfated chondroitin sulfate (OSCS) using Nuclear Magnetic Resonance (NMR) spectroscopy.
You failed to routinely establish system suitability when testing samples for OSCS.
Furthermore, on December 26, 2014, you conducted a system suitability test that failed. You did not investigate why your equipment failed system suitability for detection of OSCS, or determine the reliability of other OSCS tests conducted prior to the date of the system suitability failure.
NOTE: Their customers are not identified.
|ChemRite CoPac, Inc., June 29, 2017||Your firm failed to maintain adequate separate defined areas necessary to prevent contamination or mix-up (21 CFR 211.42(c)).|
You manufacture several over-the-counter (OTC) oral rinses and oral moisturizing drug products, including (b)(4), (b)(4) Mouth Moisturizer, and (b)(4) Oral Solution, for your customer, (b)(4) Products Inc. You manufacture these oral drug solutions using the same equipment that you use to manufacture numerous non-pharmaceutical materials in your facility, including an industrial car care product, (b)(4) Polish and Sealant.
This car care product is paraffin-based and labeled as “Harmful or fatal if swallowed” and “Keep out of reach of children.” You also manufacture other toxic non-pharmaceutical industrial and automotive care products, such as leather treatments ((b)(4) Leather Care, (b)(4) Leather Lotion) and sealants ((b)(4) Poly Sealant), using the same mixing tank and filling line you use for OTC oral drug products.
NOTE: One of their customers, Sage Products Inc, received a warning letter on July 17, 2017.
|Sage Products Inc, July 17, 2017||Drugs Made for You by ChemRite|
You have engaged ChemRite to manufacture Sage Perox-A-Mint, (b)(4). These products, which you test using the (b)(4) method discussed above, are adulterated as enumerated in the preceding violations. They are also adulterated for the reasons set forth in Warning Letter 515029, issued by FDA to ChemRite on June 29, 2017. Among other things, ChemRite manufactured your oral solution drugs using the same equipment in which ChemRite manufactured toxic industrial-grade car washes and waxes. You are responsible for ensuring that all of your products are manufactured in accordance with CGMP, including oversight of the manufacturing operations conducted by your contractor, ChemRite, on your behalf. Contractors are extensions of the manufacturer, and you are required to ensure that your drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity.
NOTE: Their contract site, ChemRite, received a warning letter on June 29, 2017.
|Homeolab USA Inc, August 2, 2017||1. Your firm failed to establish and follow adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (21 CFR 211.110(a)).|
Your firm released multiple lots of homeopathic in-process powder blends prior to attempting to validate your manufacturing process. You manufacture (b)(4) homeopathic in-process powder blend mixtures which you send to Raritan Pharmaceuticals Inc. (Raritan), a contract manufacturing organization, to produce finished homeopathic drug products for the United States (U.S.) market. Some of your powder blend mixtures are manufactured from ingredients that pose potentially toxic effects. For example, your Infants’ Teething Tablet (b)(4) contains belladonna. Raritan uses this powder blend mixture to produce finished drug products for infants and children, a population vulnerable to the toxic effects of belladonna. You shipped (b)(4) lot (b)(4) of Infants’ Teething Tablet (b)(4) to the U.S. market before evaluating whether your manufacturing process was reliable and reproducible. …
Raritan used your powder blends to contract manufacture adulterated finished drug products that you marketed for use in infants and children in the United States. FDA analysis of finished drug products made from your in-process blends also demonstrated non-homogeneous composition. …
Furthermore, it is important to note that quality agreements cannot be used to delegate statutory or regulatory responsibilities to comply with CGMP.
NOTE: Raritan Pharmaceuticals received a warning letter on June 20, 2017, but the text of the letter fails to mention their contract manufacturing operations.
|Hetero Labs Limited Unit V, August 15, 2017||Your investigations into process deviations and out-of-specification (OOS) laboratory results are insufficient, and do not include scientifically-supported conclusions.|
For example, you have acted as the contract manufacturer of (b)(4) mg (b)(4) tablets for multiple customers. In February 2016, you received a customer complaint that lot (b)(4) failed dissolution testing. During your investigation into this complaint, you noted that the (b)(4) used to manufacture lot (b)(4) was operating at up to (b)(4)% (b)(4), although its specification was not more than (NMT) (b)(4)% (b)(4). You also noted that the (b)(4) was recorded as “NMT (b)(4),” which does not indicate if the operating (b)(4) was maintained within the specification of (b)(4) ± (b)(4).
Your March 2016 Market Complaint Investigation Report concluded, without scientific justification, that the (b)(4) and possible (b)(4) deviations during the (b)(4) process for this lot had no relationship to the dissolution test failure. Although the investigation also initially concluded that the failure could be a testing issue involving the use of (b)(4) µm filters, one of your customers found this explanation unacceptable. You subsequently acknowledged to another customer that you had not identified the root cause for the failing dissolution results.
Finally, in your April 2016 Closure Report to Market Complaint Investigation, you indicated that the dissolution failure was due to the (b)(4) and (b)(4) process.
Your response states that lot (b)(4) was the only lot manufactured during a (b)(4)-lot manufacturing campaign that appeared to be affected by these processing issues. This response is inadequate because it does not provide sufficient justification for this conclusion, and fails to fully investigate the scope and root causes of the reported dissolution failure.
NOTE: Their customers are not identified.
|Meridian Medical Technologies, Inc. a Pfizer Company, September 17, 2017||Quality Agreements|
You and your customer, Mylan Specialty L.P., have a quality agreement regarding the manufacture of EpiPen products. You are responsible for the quality of combination products you produce as a contract facility, regardless of agreements in place with Mylan Specialty L.P. or with any of your suppliers. You are required to ensure that your combination products are compliant with the CGMP requirements applicable to each manufacturing process that occurs at your facility. See, generally, 21 CFR parts 4, 210, 211, and 820.
NOTE: Mylan, the sponsor for the EpiPen, has not received a warning letter on this topic.
|Accelerated Analytical Laboratories Inc., October 18, 2017||You conduct laboratory testing on over-the-counter (OTC) drug products manufactured by your clients. You perform both analytical and microbiological analysis for drug release purposes, and these activities are manufacturing operations subject to CGMP. During our inspection of your contract testing laboratory, we observed that you used laboratory methods that were not validated and suitable for their intended uses.|
According to your response, you submitted a validation protocol to your client for review and approval. Similar to your response regarding your failure to validate your microbial recovery test method for objectionable organisms, you indicated, “If the client refuses to sponsor these activities we will ensure the reports issued for the products examined in (b)(4) will be updated to note that the testing was done using unvalidated methodology.”
Your response is inadequate. Including a disclaimer on the reports you issue to your customers does not release you from the CGMP requirement that your test methods be validated and suitable for their intended use.
A contract testing laboratory must use validated methods to ensure that results of pharmaceutical analyses subject to CGMP are accurate. Your client’s certificates of analysis (CoA) reported that released drugs conformed to specifications, including microbiological specifications. Your use of test methods that were not validated as suitable for their intended uses compromised the accuracy and veracity of the information your customers provided on their CoA, and on which they relied to make release decisions.
|The contracted site from which they purchased a component [probably an API]||Aztex Enterprises Ltd. received a warning letter on October 20, 2017.|
Purchase of drugs from a manufacturer on FDA Import Alert 66-40
We reviewed a list of your suppliers, which includes (b)(4) has been listed on FDA Import Alert 66-40, Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs, since (b)(4). Import Alert 66-40 can be found on the FDA public website: https://www.accessdata.fda.gov/cms_ia/importalert_189.html. As indicated on Import Alert 66-40, drugs manufactured at (b)(4) are subject to refusal of admission to the United States because they do not conform to CGMP. Because you used adulterated materials that you purchased from a firm on Import Alert 66-40, (b)(4), the drugs you manufacture also are adulterated under the FD&C Act.
About the Author:
Barbara Unger formed Unger Consulting, Inc. in December 2014 to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including auditing and remediation in the area of data management and data integrity. Her auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Barbara was the first chairperson of the Rx-360 Monitoring and Reporting work group (2009 to 2014) that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. She also served as the chairperson of the Midwest Discussion Group GMP-Intelligence sub-group from 2010 to 2014. Barbara is currently the co-lead of the Rx-360 Data Integrity Working Group.
Before Amgen, Barbara worked for the consulting firm Don Hill and Associates, providing regulatory and quality services to the pharmaceutical industry, and for Eli Lilly and Company in quality and CMC regulatory affairs positions. She began her career in the pharmaceutical / device industry with Hybritech Inc. and received a bachelor’s degree in chemistry from the University of Illinois at Urbana-Champaign. You can contact Barbara at email@example.com.