Stem Cell Clinics

Quote from FDA Press Release on Stem Cell Clinics issued August 28, 2917:

“Stem cell clinics that mislead vulnerable patients into believing they are being given safe, effective treatments that are in full compliance with the law are dangerously exploiting consumers and putting their health at risk,” said FDA Commissioner Scott Gottlieb, M.D. “As the FDA takes new steps to advance an efficient, modern approach to the regulation of cell based regenerative medicine, at the same time we will be stepping up our enforcement actions against clinics that abuse the trust of patients and, more important, endanger their health with unsanitary conditions or by purporting to have treatments which may not provide any benefit.”

In a New York Times article also published August 28, describes the FDA crackdown on stem cell clinics.  Three stem cell clinics were inspected by the FDA.  Two of the facilities were California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills California.  The Rancho Mirage stem cell clinic received a 11-page, 11-observation 483.  The Beverly Hills stem cell clinic received a 10-page, 13-observation 483.  The third facility US Stem Cell Clinic received a 7-page 12-observation 483.

Some of the observations included:

  • Manufacturing process not validated.
  • Aseptic processes not established or followed
  • No sterility / endotoxin testing
  • No environmental monitoring
  • No identity testing of raw materials
  • No batch or production records
  • No cleaning procedures developed, followed
  • No Quality Control unit

In one case stem cells were injected into the eyes of the patients.  NYT article March 2017, also published in the New England Journal of Medicine [subscription required]. In summary, a 72 year old patient permanently lost sight in both eyes, and a 78 and 88 year old patient each lost much of their eyesight following treatment.

As identified by Willis Triplett PharmD, in his email blog (Aug 29) the FDA Oncologic Drug Advisory panel provided a unanimous (10-0) recommendation for Novartis Car T therapy and this new drug therapy may be approved very soon.  These therapies offer a unique promise of individualized medicine. However, stem cell therapy is not a panacea for every disease.  In a 2016 NEJM article the FDA share their perspective “to ensure that this emerging field fulfills its promise to patients, we must first understand its risks and benefits and develop therapeutic approaches based on sound science. Without a commitment to the principles of adequate evidence generation that have led to so much medical progress, we may never see stem-cell therapy reach its full potential.”



13-Observation 483 for Compounding Pharmacy

In a recently posted warning letter to a compounding pharmacy based on an 8-page 483 that contained 13-observation was issued following an inspection (June –July 2-16) where the FDA was responding to a reported adverse event involving Chloral Hydrate.

Examples of items identified during the FDA inspection and documented on the Form 483 include but are not limited to:

Observation 1 – there is no quality control unit.

The firm produced and distributed non-patient specific non-sterile oral liquid containing Chloral Hydrate 100mg/mL.  Review of the batch record identified the active ingredient was 10 times the amount required resulting in a super potent drug product.

The firm did not reject the drug, no potency testing is performed, and no samples were retained.

From the warning letter: FDA analysis showed that the chloral hydrate drug product contained in excess of 900% of the labeled concentration of chloral hydrate thus superpotent.

Observation 2 – The firm has not established or followed procedures to prevent microbial contamination of drug product.

Multiple issues with gowning, residue on equipment from prior processing, open trash recepticals in all of the firms classified areas, lack of validation for the autoclave for low configurations and capacities, no validation for the depyrogenation process, etc.

Observation 3 – Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

No monitoring of viable microbial contamination in the ISO-7 and ISO-5 areas during processing.  No particulate monitoring in either of these areas, no monitoring of personnel, or monitoring of differential pressures.

Observation 4 – Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

No sporicidal cleaning agents used in ISO 5 processing areas. Non Sterile wipes used to clean classified area.

Observation 8 – Routine calibration of equipment is not performed according to a written program designed to assure proper performance.

No calibration records for thermometer used to monitor dehydrogenation temperatures, the thermometer / pressure gages used in the autoclave, scales used to weigh materials used for processing were not calibrated, (linearity, accuracy, and repeatability were not tested).

Please review the 483 for additional details in each of the summarized observations as well as the observations that were not summarized.  The FDA warning letter contains additional information and actions the firm has taken subsequent to the FDA inspection.

Data Integrity – Audit Trail Review

Data integrity demands a great amount of attention in the life science industry. This is now truer than ever with increased focus from the FDA, EU, and industry standards on data integrity issues and best practices. Audit trails for computerized systems are required for all FDA / EU regulated systems. It must capture the creation, modification, and deletion of regulated electronic records. Who created and when the record must be captured, as well as who, when and why the record was modified or deleted – as relevant. When a system is validated, an audit trail should be verified to ensure accuracy and that it meets all applicable regulatory and organizational requirements. Once the system is validated and in production, the audit trail should not be forgotten. A formal process to examine the audit trail to ensure data integrity is needed in the regulated environment. Let us consider audit trail review – how to approach it and a few items of interest.

Audit trail review refers to the process of periodically examining an audit trail based on a variety of factors. It is valuable to define audit trail review based on system risk. ISPE – as recommended by ISPE in the Records and Data Integrity Guide. Place a risk level on a system just as one would for any other computerized system risk assessment using criteria such as impacts to patient safety, drug/product efficacy, quality system, business risks, complexity/criticality etc. How often and to what degree the audit trail review occurs can then be assigned. Do include all system stakeholders in the criteria and assessment process including IT, QA, and business process owners.

It is important to develop procedures and processes for audit trail review or incorporate them into a Validation Master Plan and/or Quality Management System. The review itself might only be a spot check for a very low risk system or it could be a comprehensive analysis and tracing of data and metadata. Metadata is one aspect that should not be overlooked. The audit trail review cannot be adequate (in most cases) if information that makes the data meaningful (metadata) is not available. This is a time when putting on an investigator or QA “hat” is imperative. Audit trail review should (again, based on risk level) look with scrutiny at reruns and fails of data capture and modification. Procedurally and scientifically, it may be acceptable for rerunning and failing instrument runs, for example. However, does the audit trail capture these events? If so, how and is it complete? Again, risk is key, but these are questions and answers that are important. This is also an opportune time to review training records, access controls, and general system security – as applicable.

Audit trail review is an essential component to data integrity for any computerized system. There are guidelines and industry best practices out now which are very helpful in developing a process to manage the reviews. Yet it is important to understand the system’s risk and criticality so as to approach the assessment process efficiently. Use the audit trail review to put the pieces of data capture, modification, and deletion together – using metadata to give scale and meaning to the data and information. An audit trail review may be easy to overlook or curtail, but its contribution to overall data integrity and thus patient safety is very significant.

503B Guidance

With the passage of the Compounding Quality Act, Drug Quality and Security Act of 2013 FDA defined two categories of compounding pharmacies: 503A and 503B.  This blog post is to provide 503B Guidance.

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GMP Book

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Click here to jump to the USFDA Regulatory Policy Information page that lists all the compounding facility draft and final guidance documents.

FDA’s Human Drug Compounding Progress Report: Three Years After Enactment of the Drug Quality and Security Act (January 2017) is available from the FDA here.

FDA Investigation into Compounded Products

The FDA website posted the summary of their investigation into two serious adverse events associated with ImprimisRX’s compounded curcumin emulsion product for injection.

The full summary is available on the FDA website, click here.

The short version:

Two patients were administered infusions of curcumin (a component of the spice tumeric) compounded with polyethene glycol (PEG) 40 castor oil.

One patient a female 30-year old experienced cardiac arrest, the patient suffered depleted oxygen brain injury and subsequently died.  The second patient a 71-year old male developed a hypersensitivity reaction, he was transferred to a nearby emergency room where he was treated and released.

FDA’s investigation into the adverse events associated with ImprimisRx’s curcumin emulsion product for injection highlights some of the risks associated with compounded drugs, particularly those that use non-pharmaceutical grade components and ingredients lacking a USP monograph. The risks illustrated in this case include:

  • the absence of a label warning about hypersensitivity reactions associated with the PEG 40 castor oil;
  • the use of an ungraded inactive ingredient, i.e., PEG 40 castor oil, that is not suitable for human consumption or therapeutic use and may contain impurities such as DEG; and
  • the IV administration of curcumin, despite the fact that its safety profile by this route of administration has not been established, nor has its effectiveness in treating eczema or thrombocytopenia.

Pharmacy error statistics as posted by the Hannon Legal Group:

  • Medication errors account for approximately 7000 deaths annually in hospitals alone and tens of thousands more in outpatient facilities.
  • It is estimated that between 2.2 million and 3.7 million medication dispensing errors have occurred in the U.S. in each of the past eight years which caused serious health problems or death.
  • According to the FDA, over 1.3 million people are injured each year due to medication mistakes.
  • Preventable adverse drug events (ADEs) cost the healthcare system $2 billion every year.

Isomeric Pharmacy Solutions

As posted on FDA’s website.  U.S. District Judge Robert J. Shelby entered a consent decree of permanent injunction yesterday between the United States and Isomeric Pharmacy Solutions.

According to the complaint for permanent injunction, Isomeric manufactured and distributed purportedly sterile drug products, including injectable and ophthalmic drugs that were adulterated because the drugs were made under insanitary conditions and in violation of current good manufacturing practice requirements under the FD&C Act. Drugs prepared, packed, or held under insanitary conditions may have been contaminated with filth or otherwise harmful if given to patients. The complaint also alleges that Isomeric manufactured and distributed unapproved drugs and drugs that were misbranded because their labeling did not bear adequate directions for use.

“Isomeric endangered the public health by manufacturing injectable drugs under poor conditions that compromised their required sterility and put patients at risk,” said FDA Commissioner Scott Gottlieb, M.D. “We will continue taking strong enforcement actions against compounders who violate the Drug Quality and Security Act and put patients at risk by failing to produce sterile drugs in compliance with the law.”

FDA’s post provides links to prior inspections of this registered outsourcing facility.  A 483 was issued August 2015, a second 483 issued June 2016, a warning letter posted Dec 2016, followed by a third 483 issued March 2017.

In the March 2017 483, Observation 2 identifies that 33 customer complaints were received since the previous inspection yet NONE were investigated.

  • 11-complaints were related to infection, pain, swelling or knotting at the injection site.
  • 6-complaints from clumping in the finished product.
  • 5-complaints associated with particles, fragments, or coring.

Have a question concerning the cGMPs or the FDA inspection process?

Performance Validation has printed a limited number of Pocketbook compliance guides that include 21 CFR Part 210 and 211, and the FDA’s Compliance Policy Guide which addresses the FDA inspection methodology.

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To obtain the pocketbook and information about Performance Validation simply complete the contact form.


Compounding Pharmacies were well represented in this week’s digest of Recently Posted Warning Letters.  Four of the nine letters posted were associated with compound pharmacies.

All 4 of the warning letters identified the pharmacies failed to receive valid prescriptions for individually identified patients. As we know, compounding without a valid individual prescription does not meet the conditions of 503A.  Section 503A of the FDCA describes the conditions under which human drug products compounded by a licensed pharmacist in a State licensed pharmacy or a Federal facility, or a licensed physician, qualify for exemptions from three sections of the FDCA.

Specific observations identified by the FDA in the posted warning letters include (listed in numerical order of the CFR):

  • 21 CFR 211.28(a) Inappropriate clothing worn to protect the drug product from contamination Cited 1
  • 21 CFR 211.42(b): Inadequate design of the facility to prevent contamination or mix-ups Cited 1
  • 21 CFR 211.42(c)(10(iv): Failed to establish a system to monitor environmental conditions in the aseptic processing area Cited 2
  • 21 CFR 411.42(c)(10)(v): Failed to establish a system for cleaning and disinfecting the room and equipment to produce aseptic conditions) Cited 2
  • 21 CFR 211.42 (c)(10)(vi): Failure to establish a system for maintaining equipment used to control the aseptic conditions Cited 1
  • 21 CFR 211.67(a): Failed to sanitize and/or sterilize equipment and utensils Cited 1
  • 21 CFR 211.113(b): Failed to establish and follow procedures to minimize microbiological contamination Cited 2
  • 21 CFR 211.165(a): Failure to test each batch to verify the drug product meets final specifications prior to release Cited 2
  • 21 CFR 211.165(f): Failed to reject drug product that did not meet established standards or specifications, or any other relevant quality control criteria Cited 1
  • 21 CFR 211.166(a): No Stability testing program Cited 1
  • 21 CFR 211.167(a): Failure to test each batch to verify the drug product meets final specifications for sterility and/or pyrogen Cited 1
  • 21 CFR 211.192: Failed to investigate any unexplained discrepancy Cited 1

The warning letters are available on the FDA website.  A link to each warning letter is provided below:

Please note that there is approximately a year or more between the facility inspection and posting of the warning letter.  The warning letter identified the conditions that were observed during the inspection and may not represent current conditions.

Software as a Medical Device (SaMD): Clinical Evaluation and Validation

So you have a Fitbit or activity tracker? How is it going – is it helping motivate you to move more, perhaps monitoring your heart rate? That is great – but is your doctor using the data to make decisions about your health? Probably not. However, this is the kind of question we begin to ask when considering Software as a Medical Device (SaMD). By definition, these are applications (software) intended for medical use without the use of hardware (International Medical Device Regulators Forum (IMDRF) . They are not software fixed in a medical device. “Medical use” is defined as providing “diagnosis, prevention, monitoring, treatment, or alleviation of disease/injury, supporting or sustaining life” (IMDRF guidance). SaMD can include software that might interface with hardware and/or medical devices and mobile apps that meet the definition as well. This answer, while fairly specific, can leave room for interpretation. Clinical Evaluation and categorization of the SaMD can facilitate a risk-based approach to validation.

The various guidance documents produced by the IMDRF are not intended to supersede the pre and post market regulatory requirements set forth for any medical device. SaMD is a medical device. Yet, the process of Clinical Evaluation may help drive validation requirements and a risk-based approach. SaMD Clinical Evaluation is the process to assess “the analytical validity (the SaMD’s output is accurate for a given input), and where appropriate, the scientific validity (the SaMD’s output is associated to the intended clinical condition/physiological state), and clinical performance (the SaMD’s output yields a clinically meaningful association to the target use of the SaMD) of the SaMD.” IMDRF guidance). Each validity check has a specific aim and outcome. Validation is part of the process of creating confirmation of analytical validity. In practice, the already required process of computer system validation can feed into the Clinical Evaluation. IMDRF guidance even states:  “analytical validity evidence of a SaMD is generated during the verification and validation activities in a manufacturer’s quality management system process and is always expected for a SaMD.” The IMDRF offers a risk categorization framework document. They define four categories. These are based on the “state of health care situation or condition (critical, serious, non-serious)” and the “significance of the information provided by SaMD to healthcare division (treat or diagnose, drive clinical management, and inform clinical management)” (IMDRF guidance). It is advisable to use this categorization to drive the risk-based process for verification and validation, particularly for the rigor of evidence gathering. The GAMP 5 process to risk-based computer system validation is likely to be of use here.

Validation of Software as a Medical Device is essentially no different than the validation of any computerized system. It is best to think of it in this way. However, one cannot simply put up “blinders” and ignore the singularity of a SaMD when assessing risk and right-sizing one’s validation effort.


In a recently posted warning letter, the manufacturer of over-the-counter (OTC) oral rinses and oral moisturizing drug products received a citation concerning 21 CFR 211.42.

The firm used the same manufacturing equipment to manufacture the GMP over-the-counter oral rinses and oral moisturizing drug products and numerous non-pharmaceutical materials (Co-Manufacturing) in your facility, including an industrial car care product, [redacted] polish and sealant.  As noted in the warning letter, the car care product is paraffin-based and labeled as “Harmful or fatal if swallowed” and “Keep out of reach of children.”  Additionally – the company manufactures leather treatments [redacted] Leather Care, [redacted] Leather Lotion) and sealants [redacted] Poly Sealant, using the same mixing tank and filling line used for OTC oral drug products (co-manufacturing).

This firm was also cited for failure to have adequate laboratory testing 21 CFR 211.165b.  As identified in the warning letter the firm released 24 batches of OTC drug products between 2013 and 2015 without performing analyses to assess whether they met all microbiological finished product specifications.

Lastly – the firm was cited for not having an adequate quality control unit 21 CFR 211.22a.  In this case the firm’s oversight of drugs manufactured by the firm, and testing provided by the contract laboratory was inadequate.  The FDA identified the contact testing laboratory had not validated the test method used to detect Burkholderia Cepacia. This inspection occurred in July of 2016.  However, the firm had similar issues identified by FDA in inspections conducted in 2013 and 2016  which only supports the inference that the firm’s quality unit is not adequate.

While a different scenario, the potential for cross contamination between industrial and GMP (co-manufacturing) is documented in the FDA’s Validation of Cleaning Processes (7/93):

One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.


CDRH Calendar Year 2016 Data

Calendar year data for the Center for Devices and Radiological Heath data has been released and is available here.

Some highlights from the report:
  • There were 1450 Domestic and 725 Foreign inspections in 2016.
  • Overall 52% of the inspections resulted in NAI – No Action Indicated, 39% resulted in Voluntary Action Indicated, and 9% resulted in Official Action Indicated.
  • 854 FDA Form 483s, containing 3,027 citations for 21 CFR 820 were issued in 2016
  • Hot topics on all inspections for each of the quality system elements included:
    • CAPA 1017 observations 34%
    • Production and Process Controls 964 observations 32%
    • Design Control 382 observations 13%
    • Management 347 observations 11%
    • Document Controls 317 10%